JP2021020948A - Kras g12c inhibitors and methods of using the same - Google Patents

Abstract

To provide KRAS G12C inhibitors, composition of the same, and methods of using the same, useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.SOLUTION: The present invention relates to a compound having the structure of the following formula, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, or a compound having a similar structure to the structure of the following formula.SELECTED DRAWING: None

Description

The present specification provides KRAS G12C inhibitors, compositions thereof, and methods of use thereof. These inhibitors are useful for treating a number of disorders, including pancreatic cancer, colon cancer, and lung cancer.

KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colon cancer, gallbladder cancer, thyroid cancer, and cholangiocarcinoma. KRAS mutations are also found in about 25% of NSCLC patients, and some studies have shown that KRAS mutations are a poor prognostic factor in NSCLC patients. Recently, V-Ki-ras2 Karsten rat sarcoma virus oncogene homologue (KRAS) mutations have been found to confer resistance to treatments targeting epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, important information can be obtained from the mutant state of KRAS prior to the prescription of TKI treatment. In summary, patients with pancreatic, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed with such cancers characterized by KRAS mutations, have progressed after chemotherapy. There is a need for new chemotherapy for patients, including patients.

［式中、
Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、Ｃ_１−６アルコキシ、ＮＨ−Ｃ_１−６アルキル、Ｎ（Ｃ_１〜６アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１−６アルキル、Ｃ_１−６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、シクロアルクリル、ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成する］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。

[During the ceremony,
E ¹ and E ² are independently N or CR ¹ , respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-6 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1-6 alkyl, C 1-6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _{0-3alkylenearyl} , or C _0-3alkylene heteroaryl, where each _R'is independent of H, C. _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or two R'substituents bond with each other together with the nitrogen atoms they bind to to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 6 alkyl, C 2 to 6 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} haloalkyl, cycloalkyl alk Lil, Heterocycloalkyl, C _0-3alkylene- C _3-4 cycloalkyl, C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl , Or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bond with each other with the atoms to which they bind to form a 4- to 6-membered ring, and R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ with the atom to which they bind Combine to form a 4- to 6-membered ring]
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

［式中、
Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、ＮＨ−Ｃ_１〜６アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜１４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^７はＨもしくはＣ_１〜６アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成する］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。 In another embodiment, the specification is set forth in formula (I).

[During the ceremony,
E ¹ and E ² are independently N or CR ¹ , respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or The two R'substituents bond with each other together with the nitrogen atom they bind to to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-14 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bond with each other with the atoms to which they bind to form a 4- to 6-membered ring, and R ⁷ is H or C _{1 to 6} alkyl, or R ⁷ and R ⁵ with the atom to which they bind together. Combine to form a 4- to 6-membered ring]
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

［式中、Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
ＪはＮ、ＮＲ^１０、またはＣＲ^１０であり、
ＭはＮ、ＮＲ^１３、またはＣＲ^１３であり、

は各原子にその通常の原子価を与えるよう必要に応じ単結合または二重結合であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、シクロアルクリル、ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、もしくはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９はそれぞれ独立してＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、シアノ、ニトロ、もしくはＣ_３〜６シクロアルキルであるか、またはＲ^８及びＲ^９はそれらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンであり、かつ
Ｒ^１３はＣ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、もしくはＣ_３〜１４シクロアルキルであるか、
またはその薬学的に許容される塩であるが、
（１）ＪがＮＲ^１０の場合、ＭはＮまたはＣＲ^１３であり、
（２）ＭがＮＲ^１３の場合、ＪはＮまたはＣＲ^１０であり、
（３）ＪがＣＲ^１０の場合、ＭはＮまたはＮＲ^１３であり、かつ
（４）ＭがＣＲ^１３の場合、ＪはＮまたはＮＲ^１０である］
の化合物、またはその薬学的に許容される塩を提供する。 Furthermore, equation (II)

[In the formula, E ¹ and E ² are independently N or CR ¹ , respectively.
J is N, NR ¹⁰ , or CR ¹⁰ .
M is N, NR ¹³ , or CR ¹³ .

Is a single or double bond as needed to give each atom its normal valence,
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, Aryl, or heteroaryl,
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} haloalkyl, cycloalkyl alk Lil, _{heterocycloalkyl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, aryl, _heteroaryl, or a _{C 0 to 3} alkylene _{-C having 6 to 14} aryl , Or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
R ⁸ and R ⁹ are independently H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, cyano, nitro, or C _3-6 cycloalkyl, respectively, or R ⁸ and R ⁹ are they. It can be bonded to each other together with the carbon atoms to be bonded to form a 3- to 6-membered ring.
R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, C _0-3 alkylene-C _3-14 heteroaryl, C _0-3 alkylene-C _3-14 cycloalkyl, C _{0 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _{O-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene _{-C 2 to 14 heterocycloalkyl, NH-C} 1~8 alkyl, _{N (C 1 to 8 alkyl)} 2, _{NH-C 0~ 3} alkylene _{-C having 6 to 14} aryl, _NH-C 0~3 alkylene _{-C 2 to 14} heteroaryl, _NH-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _NH-C 0~3 alkylene _{-C. 2 to 14} heterocycloalkyl, halo, cyano, or C _1-6 alkylene-amine, and R ¹³ is C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyleneamine, or C _3-14 cycloalkyl. Is
Or its pharmaceutically acceptable salt,
(1) When J is NR ¹⁰ , M is N or CR ¹³ .
(2) When M is NR ¹³ , J is N or CR ¹⁰ .
(3) When J is CR ¹⁰ , M is N or NR ¹³ , and (4) When M is CR ¹³ , J is N or NR ^10. ]
Provided, or a pharmaceutically acceptable salt thereof.

In some embodiments, if Q is C = O and E ¹ and E ² are CR ¹ , respectively, then (1) R ¹⁰ is C _1-3 alkylene aryl, C _1-3 alkylene heteroaryl. , C _0-3 alkylene-C _3-8 cycloalkyl, C _1-3 alkylene-C _2-7 heterocycloalkyl, or halo, or (2) R ¹³ is C _1-3 haloalkyl or C _{3 ~} It is either ₅ cycloalkyl. In various embodiments, J is NR ¹⁰ and M is CR ¹³ . In some embodiments, J is CR ¹⁰ and M is NR ¹³ . In some embodiments, J is N and M is NR ¹³ . In various embodiments, J is NR ¹⁰ and M is N.

［式中、
Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
ＪはＮ、ＮＲ^１０、またはＣＲ^１０であり、
ＭはＮ、ＮＲ^１３、またはＣＲ^１３であり、

は各原子にその通常の原子価を与えるよう必要に応じ単結合または二重結合であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、またはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９はそれぞれ独立してＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、シアノ、ニトロ、もしくはＣ_３〜６シクロアルキルであるか、またはＲ^８及びＲ^９はそれらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンであるが、
（１）ＪがＮＲ^１０の場合、ＭはＮまたはＣＲ^１３であり、
（２）ＭがＮＲ^１３の場合、ＪはＮまたはＣＲ^１０であり、
（３）ＪがＣＲ^１０の場合、ＭはＮまたはＮＲ^１３であり、かつ
（４）ＭがＣＲ^１３の場合、ＪはＮまたはＮＲ^１０である］
の構造を有する化合物を提供する。 Furthermore, equation (II)

[During the ceremony,
E ¹ and E ² are independently N or CR ¹ , respectively.
J is N, NR ¹⁰ , or CR ¹⁰ .
M is N, NR ¹³ , or CR ¹³ .

Is a single or double bond as needed to give each atom its normal valence,
R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
R ⁸ and R ⁹ are independently H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, cyano, nitro, or C _3-6 cycloalkyl, respectively, or R ⁸ and R ⁹ are they. It can be bonded to each other together with the carbon atoms to be bonded to form a 3- to 6-membered ring.
R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, C _0-3 alkylene-C _3-14 heteroaryl, C _0-3 alkylene-C _3-14 cycloalkyl, C _{0 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _{O-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene _{-C 2 to 14 heterocycloalkyl, NH-C} 1~8 alkyl, _{N (C 1 to 8 alkyl)} 2, _{NH-C 0~ 3} alkylene _{-C having 6 to 14} aryl, _NH-C 0~3 alkylene _{-C 2 to 14} heteroaryl, _NH-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _NH-C 0~3 alkylene _{-C. 2 to 14} Heterocycloalkyl, halo, cyano, or C _1-6 alkylene-amine,
(1) When J is NR ¹⁰ , M is N or CR ¹³ .
(2) When M is NR ¹³ , J is N or CR ¹⁰ .
(3) When J is CR ¹⁰ , M is N or NR ¹³ , and (4) When M is CR ¹³ , J is N or NR ^10. ]
Provided is a compound having the structure of.

In some embodiments, if Q is C = O and E ¹ and E ² are CR ¹ , respectively, then (1) R ¹⁰ is C _1-3 alkylene aryl, C _1-3 alkylene heteroaryl. , C _0-3 alkylene-C _3-8 cycloalkyl, C _1-3 alkylene-C _2-7 heterocycloalkyl, or halo, or (2) R ¹³ is C _1-3 haloalkyl or C _{3 ~} It is either ₅ cycloalkyl. In various embodiments, J is NR ¹⁰ and M is CR ¹³ . In some embodiments, J is CR ¹⁰ and M is NR ¹³ . In some embodiments, J is N and M is NR ¹³ . In various embodiments, J is NR ¹⁰ and M is N.

［式中、Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、シクロアルクリル、ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、またはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９はそれぞれ独立してＨ、Ｃ_１〜６アルキル、ヒドロキシ、Ｃ_１〜６アルコキシ、シアノ、ニトロ、もしくはＣ_３〜１４シクロアルキルであるか、またはＲ^８及びＲ^９はそれらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンである］
の化合物、またはその薬学的に許容される塩を提供する。 In addition, equation (III) or (III')

[In the formula, E ¹ and E ² are independently N or CR ¹ , respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, Aryl, or heteroaryl,
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} haloalkyl, cycloalkyl alk Lil, _{heterocycloalkyl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, aryl, _heteroaryl, or a _{C 0 to 3} alkylene _{-C having 6 to 14} aryl , Or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
R ⁸ and R ⁹ are independently H, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, cyano, nitro, or C _3-14 cycloalkyl, or R ⁸ and R ⁹ are they. It can be bonded to each other together with the carbon atoms to be bonded to form a 3- to 6-membered ring.
R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, C _0-3 alkylene-C _3-14 heteroaryl, C _0-3 alkylene-C _3-14 cycloalkyl, C _{0 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _{O-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene _{-C 2 to 14 heterocycloalkyl, NH-C} 1~8 alkyl, _{N (C 1 to 8 alkyl)} 2, _{NH-C 0~ 3} alkylene _{-C having 6 to 14} aryl, _NH-C 0~3 alkylene _{-C 2 to 14} heteroaryl, _NH-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _NH-C 0~3 alkylene _{-C. 2 to 14} Heterocycloalkyl, halo, cyano, or C _1-6 alkylene-amine]
Provided, or a pharmaceutically acceptable salt thereof.

［式中、
Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、またはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９はそれぞれ独立してＨ、Ｃ_１〜６アルキル、ヒドロキシ、Ｃ_１〜６アルコキシ、シアノ、ニトロ、もしくはＣ_３〜１４シクロアルキルであるか、またはＲ^８及びＲ^９はそれらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンである］
の化合物、またはその薬学的に許容される塩を提供する。 In addition, formula (III) or (III')

[During the ceremony,
E ¹ and E ² are independently N or CR ¹ , respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, Aryl, or heteroaryl,
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
R ⁸ and R ⁹ are independently H, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, cyano, nitro, or C _3-14 cycloalkyl, or R ⁸ and R ⁹ are they. It can be bonded to each other together with the carbon atoms to be bonded to form a 3- to 6-membered ring.
R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, C _0-3 alkylene-C _3-14 heteroaryl, C _0-3 alkylene-C _3-14 cycloalkyl, C _{0 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _{O-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene _{-C 2 to 14 heterocycloalkyl, NH-C} 1~8 alkyl, _{N (C 1 to 8 alkyl)} 2, _{NH-C 0~ 3} alkylene _{-C having 6 to 14} aryl, _NH-C 0~3 alkylene _{-C 2 to 14} heteroaryl, _NH-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _NH-C 0~3 alkylene _{-C. 2 to 14} Heterocycloalkyl, halo, cyano, or C _1-6 alkylene-amine]
Provided, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has a structure of formula (III). In other embodiments, the compound has a structure of formula (III').

The compounds of formula (II) or (III) disclosed herein may have one or more of the following characteristics: In some embodiments, Q is C = O. In some embodiments, Q is C = S. In some embodiments, Q is C = NR ⁸ . In various embodiments, R ⁸ is a C _1-2 alkyl. In some embodiments, the Q is CR ⁸ R ⁹ . In various embodiments, Q is C = CR ⁸ R ⁹ . In some embodiments, R ⁸ and R ⁹ bond with each other together with the carbon atoms to which they bind to form a 3- to 4-membered ring. In some embodiments, R ⁸ is C _1-2 alkyl and R ⁹ is H.

［Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、ＮＨ−Ｃ_１〜６アルキル、Ｎ（Ｃ_１〜６アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、シクロアルクリル、ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^８はＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、ハロ、シアノ、ニトロ、Ｃ_３〜１４シクロアルキル、またはＮＲ^１１Ｒ^１２であり、
Ｒ^１１及びＲ^１２はそれぞれ独立してＨ、Ｃ_１〜８アルキル、またはＣ_３〜１４シクロアルキルであり、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、Ｎ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｎ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンである］
の化合物、またはその薬学的に許容される塩も提供する。 Equation (IV) or (IV')

[E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-6 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} haloalkyl, cycloalkyl alk Lil, _{heterocycloalkyl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, aryl, _heteroaryl, or a _{C 0 to 3} alkylene _{-C having 6 to 14} aryl , Or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
R ⁸ is H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, halo, cyano, nitro, C _3-14 cycloalkyl, or NR ¹¹ R ¹² .
R ¹¹ and R ¹² are independently H, C _1-8 alkyl, or C _3-14 cycloalkyl, and R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, respectively. C _{0 to 3} alkylene _{-C 2 to 14 heteroaryl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _{O-C 0 to 3} alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 2 to 14} heteroaryl, _O-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene -C _{2 ~ 14} Heterocycloalkyl, NH-C _1-8 alkyl, N (C _1-8 alkyl) ₂ , NH-C _0-3alkylene -C _6-14 aryl, NH-C _0-3alkylene -C _2-14 heteroaryl, _{N-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _{N-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, halo, cyano, or _{C 1 to 6} alkylene - amine]
Compounds, or pharmaceutically acceptable salts thereof, are also provided.

In some embodiments, the compounds disclosed herein have the structure of formula (IV). In various embodiments, the compounds disclosed herein have a structure of formula (IV'). In some embodiments, E ¹ and E ² are CR ¹ respectively and R ⁸ is hydroxy, halo, nitro, or C _3-6 cycloalkyl.

［式中、
Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、ＮＨ−Ｃ_１〜６アルキル、Ｎ（Ｃ_１〜６アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜１４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^８はＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、ハロ、シアノ、ニトロ、Ｃ_３〜１４シクロアルキル、またはＮＲ^１１Ｒ^１２であり、
Ｒ^１１及びＲ^１２はそれぞれ独立してＨ、Ｃ_１〜８アルキル、またはＣ_３〜１５シクロアルキルであり、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレン−アミンである］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。 In some embodiments, R ⁸ is methyl. In addition, formula (IV) or (IV')

[During the ceremony,
E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-6 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-14 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
R ⁸ is H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, halo, cyano, nitro, C _3-14 cycloalkyl, or NR ¹¹ R ¹² .
R ¹¹ and R ¹² are independently H, C _1-8 alkyl, or C _3-15 cycloalkyl, and R ¹⁰ is C _1-8 alkyl, C _0-3 alkylene-C _6-14 aryl, respectively. C _{0 to 3} alkylene _{-C 3 to 14 heteroaryl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 1 to 6} alkoxy, _{O-C 0 to 3} alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _O-C 0~3 alkylene _{-C 3 to 14} cycloalkyl, _O-C 0~3 alkylene -C _{2 ~ 14} Heterocycloalkyl, NH-C _1-8 alkyl, N (C _1-8 alkyl) ₂ , NH-C _0-3alkylene -C _6-14 aryl, NH-C _0-3alkylene -C _2-14 heteroaryl, _{NH-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _{NH-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, halo, cyano, or _{C 1 to 6} alkylene - amine]
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds disclosed herein have the structure of formula (IV). In various embodiments, the compounds disclosed herein have a structure of formula (IV'). In some embodiments, E ¹ and E ² are CR ¹ respectively and R ⁸ is hydroxy, halo, nitro, or C _3-6 cycloalkyl.

In some embodiments, R ⁸ is methyl.

［式中、
Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、ＮＨ−Ｃ_１〜６アルキル、Ｎ（Ｃ_１〜６アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、Ｃ_３〜１４シクロアルキル、Ｃ_２〜６アルケニル、Ｃ_２〜６アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、シクロアルクリル、ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、もしくはＣ_１〜６アルキレン−アミンであるか、またはその薬学的に許容される塩である］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。 Furthermore, equation (V)

[During the ceremony,
E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-6 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-14 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} haloalkyl, cycloalkyl alk Lil, _{heterocycloalkyl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, aryl, _heteroaryl, or a _{C 0 to 3} alkylene _{-C having 6 to 14} aryl , Or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ are bonded together with the atoms to which they are attached to form a 4- to 6-membered ring, and R ¹⁰ is C _{1 to 8} alkyl, C _{0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 3 to 14 heteroaryl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocyclo _{alkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _O-C 0~3 alkylene _{-C 3 to 14} cycloalkyl alkyl, _{O-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, _{NH-C 1 to 8} alkyl, _{N (C 1 to 8 alkyl)} 2, _NH-C 0~3 alkylene _{-C having 6 to 14} aryl, _{NH-C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, _{NH-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _{NH-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, halo, cyano, Alternatively, it is a C _1-6 alkylene-amine, or a pharmaceutically acceptable salt thereof].
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

［式中、
Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、ＮＨ−Ｃ_１〜６アルキル、Ｎ（Ｃ_１〜６アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、またはＣ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜１４シクロアルキル、Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルコキシ、Ｃ_３〜１４シクロアルキル、Ｃ_２〜８アルケニル、Ｃ_２〜８アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜６アルキル、Ｃ_２〜６アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレン−アミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜８アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４ヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_６〜１４アリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜１４シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜１４ヘテロシクロアルキル、ハロ、シアノ、もしくはＣ_１〜６アルキレン−アミンであるか、またはその薬学的に許容される塩である］
の構造を有する化合物を提供する。 Furthermore, equation (V)

[During the ceremony,
E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, NH-C _1-6 alkyl, N (C _1-6 alkyl) ₂ , cyano, or halo. And
R ² is _{halo, C 1 to 6 alkyl, C 1 to 6} haloalkyl, OR ', N (R' ) 2, C 2~3 _{alkenyl, C 2 to 3 alkynyl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl _Alkyne , C _0-3alkylene- C _2-14 heterocycloalkyl, aryl, heteroaryl, C _0-3alkylene- C _6-14 aryl, or C _0-3alkylene- C _2-14 heteroaryl, each _R'is independent of each other, H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, Alternatively, they may be heteroaryl, or the two R'substituents may combine with the nitrogen atom to which they are attached to form a 3- to 7-membered ring.
R ³ is halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-14 cycloalkyl, C _2-8 alkenyl, C _2-8 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ⁵ and R ⁶ are independently H, halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} Haloalkyl, C _{1-6 Arylamine} , C _0-6 alkylene-amide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _{1 ~ 6} alkylene -O- _{aryl, C 0 to 3} alkylene -C _{(O) C} 1~4 alkylene -OH, cycloalkyl, heterocycloalkyl, aryl, _{heteroaryl, C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, C _{0 to 3} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, or whether it is cyano, or ^{R 5} and R ⁶ bonds together with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-8 alkyl, or R ⁷ and R ⁵ are bonded together with the atoms to which they are attached to form a 4- to 6-membered ring, and R ¹⁰ is C _{1 to 8} alkyl, C _{0 to 3} alkylene _{-C having 6 to 14 aryl, C 0 to 3} alkylene _{-C 3 to 14 heteroaryl, C 0 to 3} alkylene _{-C 3 to 14 cycloalkyl, C 0 to 3} alkylene _{-C 2 to 14} heterocyclo _{alkyl, C 1 to 6} alkoxy, _O-C 0~3 alkylene _{-C having 6 to 14} aryl, _O-C 0~3 alkylene _{-C 3 to 14} heteroaryl, _O-C 0~3 alkylene _{-C 3 to 14} cycloalkyl alkyl, _{O-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, _{NH-C 1 to 8} alkyl, _{N (C 1 to 8 alkyl)} 2, _NH-C 0~3 alkylene _{-C having 6 to 14} aryl, _{NH-C 0 to 3} alkylene _{-C 2 to 14} heteroaryl, _{NH-C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl, _{NH-C 0 to 3} alkylene _{-C 2 to 14} heterocycloalkyl, halo, cyano, Alternatively, it is a C _1-6 alkylene-amine, or a pharmaceutically acceptable salt thereof].
Provided is a compound having the structure of.

The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have. In some embodiments, each of E ¹ and E ² is CR ¹ . In other embodiments, E ¹ is CR ¹ and E ² is N. In some embodiments, E ¹ is N and E ² is CR ¹ . In various embodiments, each of E ¹ and E ² is N.

であり得る。 The compounds of formulas (II), (III), (III'), (IV), (IV'), or (V) disclosed herein may have one or more of the following characteristics: In various embodiments, R ¹⁰ is C _1-6 alkyl, aryl, heteroaryl, C _3-14 cycloalkyl, C _2-14 heterocycloalkyl, C _1-6 alkoxy, _{OC 0-6} alkylene-C. _{6-14 aryl, O-C} 0~6 alkylene _{-C 2 to 14 heteroaryl, O-C} 0~6 alkylene _{-C 3 to 14 cycloalkyl, O-C} 0~6 alkylene _{-C 2 to 14} heterocycloalkyl , _{NC 1-8} alkyl, N (C _1-8 alkyl) ₂ , NH-C _0-6 alkylene-C _6-14 aryl, NH-C _0-6 alkylene-C _2-14 heteroaryl, NH- C _0-6 alkylene-C 3 to ₁₄ cycloalkyl, or NH-C _{0 to 6} alkylene-C _{2 to 14} heterocycloalkyl. In various embodiments, R ¹⁰ is C _1-8 alkyl. In some embodiments, R ¹⁰ is C _0-3alkylene- C _6-14 aryl. In some embodiments, R ¹⁰ is C _0-3 alkylene-C _2-14 heteroaryl. In some ^{embodiments, R 10} is _{C 0 to 3} alkylene _{-C 3 to 14} cycloalkyl. In some embodiments, R ¹⁰ is C _0-3 alkylene-C _2-14 heterocycloalkyl. In other embodiments, R ¹⁰ is a C _0-6 alkylene amine. For example, R ¹⁰ is i-Pr, t-Bu, phenyl, benzyl, OCH ₃ , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Can be.

であり得る。 In some embodiments, R ¹⁰ comprises an ortho-substituted aryl, an ortho-substituted heteroaryl, or a di-substituted cyclohexyl. For example, R ¹⁰

Can be.

The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have. In some embodiments, R ¹ is H. In some embodiments, R ¹ is F. In some embodiments, R ¹ is methyl.

であり得る。 The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have. In various embodiments, R ² is aryl. In some embodiments, R ² is heteroaryl. In various embodiments, R ² is phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indrinyyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazolyryl, pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, Kinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl. For example, R ² is Cl, Br, CF ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, OCH ₃ , OCH ₂ CH ₃ , phenyl,

Can be.

であり得る。 In various embodiments, R ² is bromine,

Can be.

The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have. In various embodiments, R ³ is halo. In various embodiments, R ³ is Cl. In various embodiments, R ³ is F. In some embodiments, R ³ is a C _1-2 alkyl. In some embodiments, R ³ is methyl. In some embodiments, R ³ is C _1-2 haloalkyl. In various embodiments, R ³ is CF ₃ .

である。さまざまな実施形態では、Ｒ^４は

である。いくつかの実施形態では、Ｒ^４は

である。いくつかの実施形態では、Ｒ^４は

である。いくつかの実施形態では、Ｒ^４は

である。いくつかの実施形態では、Ｒ^４は

である。いくつかの実施形態では、Ｒ^４は、

であり得る。 The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have. In some embodiments, R ⁴ is

Is. In various embodiments, R ⁴ is

Is. In some embodiments, R ⁴ is

Is. In some embodiments, R ⁴ is

Is. In some embodiments, R ⁴ is

Is. In some embodiments, R ⁴ is

Is. In some embodiments, R ⁴ is,

Can be.

から選択される。 In various embodiments, R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6} Haloalkyl, C _0-3alkylene- C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3alkylene- C _6-14 aryl, or

Is selected from.

であり得る。 In various embodiments,

Can be.

である。 In some embodiments, the ring A is

Is.

In some embodiments, ring A comprises piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In some embodiments, ring A comprises piperidinyl.

であり得る。 In various embodiments, the ring A is

Can be.

であり得る。 In various embodiments, the ring A is

Can be.

The compounds of formulas (I), (II), (III), (III'), (IV), (IV'), or (V) disclosed herein have one or more of the following characteristics: Can have.

In some embodiments, L is a bond.

In some embodiments, L is C _1-2 alkylene.

In various embodiments, L is O. In some embodiments, L is S.

In various embodiments, L is NH.

In some embodiments, R ⁵ is H or halo.

である。 In some embodiments, R ⁵ is H, Br, Cl, F, CN, CH ₃ , CF ₃ , CH ₂ Br, CH ₂ OH, CH ₂ CH ₂ OH, CH ₂ OCH ₂ phenyl, cyclopropyl, phenyl. , CH ₂ phenyl, CH ₂ OCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ N (CH ₂ CH ₃ ) ₂ , CH ₂ CO ₂ H, CH ₂ CO ₂ CH ₃ , CH ₂ NHC (O) CH ₃ , CH ₂ C (O) NHCH ₃ , CH ₂ OC (O) CH ₃ , or

Is.

In some embodiments, R ⁶ is C _1-6 alkyl, C _1-6 alkylene-OC _1-6 alkyl, C _1-6 alkylene-OH, C _1-3 haloalkyl, C _1-6 alkylene- _{amine, C Less than six} alkylene - _{amide, C 0 to 1} alkylene _{C (O) OC} 1~3 _{alkyl, C 0 to 1} alkylene _{-C 2 to 14 heterocycloalkyl, C 0 to 1} alkylene _{-C 3 to 14} cycloalkyl Alkyl, or C _0-3 alkylene-C _6-14 aryl.

である。

Is.

である。 In various embodiments, R ⁶ is phenyl, cyclopropyl, CH ₃ , CF ₃ , CH ₂ CH ₃ , CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH (CH ₃ ) ₂ NH ₂ , CH ₂ Cl. , CH ₂ Br, CH ₂ OCH ₃ , CH ₂ Ophenyl, CH ₂ OH, CO ₂ H, CO ₂ CH ₂ CH ₃ , CH ₂ CO ₂ H, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ OH, CH ₂ CH ₂ N (CH ₃ ) ₂ , CH ₂ NHCH ₃ , C (O) NHCH ₃ , C (O) N (CH ₃ ) ₂ , CH ₂ C (O) NHphenyl, CH ₂ CHF ₂ , CH ₂ F , CHF ₂ , CH ₂ NHC (O) CH ₃ , CH ₂ NHCH ₂ CH ₂ OH, CH ₂ NHCH ₂ CO ₂ H, CH ₂ NH (CH ₃ ) CH ₂ CO ₂ CH ₃ , CH ₂ NHCH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ C (O) N (CH ₃ ) ₂ , CH ₂ NH (CH ₃ ) CH ₂ C (O) NHCH ₃ , CH ₂ CH ₂ CCH, CH ₂ NMe ₂ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OH, CH ₂ NH (CH ₃ ) CH ₂ CH ₂ F, CH ₂ N ⁺ (CH ₃ ) ₃ , CH ₂ NHCH ₂ CHF ₂ , CH ₂ NHCH ₂ CH ₃ ,

Is.

である。 In various embodiments, taken with R ⁵ and R ⁶ together,

Is.

In some embodiments, each of R ⁵ and R ⁶ is H.

In some embodiments, R ⁷ is H.

In some embodiments, R ⁷ is methyl.

In various embodiments, R ⁷ and R ⁵ are combined to be -CH _2- or -C (O) CH _2- .

The compounds disclosed herein can be in pharmaceutically acceptable salt form. The provided compound can be formulated into a pharmaceutical formulation containing the compounds disclosed herein and a pharmaceutically acceptable excipient.

It also provides a method of inhibiting KRAS G12C in cells, which comprises contacting such cells with a compound or composition disclosed herein. In addition, it provides a method of treating cancer in a subject, which comprises administering to such subject a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

Definition Abbreviations: The following abbreviations may be used herein.

The use of the terms "a", "an" and "the", as well as similar directives in the description of the invention (especially in the following claims), shall be construed as including both singular and plural unless otherwise specified. Will be done. The details of the numerical range herein are used as a simplified method of individually referring to each of the distinct values that fall within that range, unless otherwise specified herein. Each is incorporated herein as if it were individually cited herein. All examples described herein, or the use of exemplary language (eg, "like"), are intended to make this application clearer, unless otherwise stated in the claims. , The scope of the present invention is not limited. No wording in the specification should be construed as indicating any non-patented element as an integral part of the practice of the present invention.

As used herein, the term "alkyl" refers to straight chain and branched _{C1-C 8} hydrocarbon groups which for methyl, ethyl, n- propyl, i- propyl, n- butyl, sec- Butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl , 2,3-Dimethylbutyl, 3,3-dimethylbutyl, and 2-Etibutyl, but are not limited thereto. The term C _mn means that the alkyl group has "m" to "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. Alkyl (e.g., methyl) groups or alkylene (e.g., -CH 2 _-), groups are independently selected, for example, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -NC, amino, -CO ₂ H, -CO ₂ C _1- C ₈ alkyl, -OCOC _1- C ₈ alkyl, C _3- It can be substituted with one or more, typically 1-3, of C ₁₀ cycloalkyl, C _3- C ₁₀ heterocycloalkyl, C _5- C ₁₀ aryl, and C _5- C ₁₀ heteroaryl. The term "haloalkyl" specifically refers to an alkyl group in which at least one, for example, 1 to 6, or all of the hydrogen of the alkyl group is substituted with a halo atom.

The terms "alkenyl" and "alkynyl" each refer to an alkyl group further comprising a double or triple bond.

As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodine. The term "alkoxy" is defined as -OR where R is alkyl.

が挙げられる。 As used herein, the terms "amino" or "amine" interchangeably refer to _two -NR groups, where each R is, for example, H or a substituent. In some embodiments, further substituted by ammonium ions amino group, for example, to form a NR ₃ ^+. The ammonium moiety is specifically included in the definition of "amino" or "amine". The substituent can be, for example, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an amide group, or a carboxylate group. The R group may be further substituted, for example, halo group, cyano group, alkenyl group, alkynyl group, alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, urea group, carbonyl group, carboxylate. It may be substituted with one or more selected from groups, amine groups, and amide groups, for example 1 to 4 groups. The "amide" or "amide" groups are compatible and similar to amine or amino groups, but also include C (O), eg, -C (O) NR ₂ . Refers to the group. CH ₂ NH ₂ , CH (CH ₃ ) NH ₂ , CH as part of the intended amino group or amide group (optionally having an alkylene group, for example, alkylene-amino, or alkylene-amide). (CH ₃ ) ₂ NH ₂ , CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ N (CH ₃ ) ₂ , CH ₂ NHCH ₃ , C (O) NHCH ₃ , C (O) N (CH ₃ ) ₂ , CH ₂ C (O) NHphenyl, CH ₂ NHC (O) CH ₃ , CH ₂ NHCH ₂ CH ₂ OH, CH ₂ NHCH ₂ CO ₂ H, CH ₂ NH (CH ₃ ) CH ₂ CO ₂ CH ₃ , CH ₂ NHCH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ C (O) N (CH ₃ ) ₂ , CH ₂ NH (CH ₃ ) CH ₂ C (O) NHCH ₃ , CH ₂ CH ₂ CCH, CH ₂ NMe ₂ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OH, CH ₂ NH (CH ₃ ) CH ₂ CH ₂ F, CH ₂ N ⁺ (CH ₃₎ ) ₃ , CH ₂ NHCH ₂ CHF ₂ , CH ₂ NHCH ₂ CH ₃ ,

Can be mentioned.

As used herein, the term "aryl" is a C _6-14 monocyclic or polycyclic aromatic group, preferably a C _6-10 monocyclic or bicyclic aromatic group, or C. _{10 to 14} Polycyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to C- _10-14 bicyclic and tricyclic carbocycles, where one ring is an aromatic ring and the other is a saturated, partially unsaturated, or aromatic ring. For example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). Unless otherwise stated, the aryl groups are independent of each other, eg, halo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -CF ₃ , -OCF ₃ , -NO ₂ , -CN. , -NC, -OH, alkoxy, amino, -CO ₂ H, -CO ₂ C _1- C ₈ alkyl, -OCOC _1- C ₈ alkyl, C _3- C ₁₀ cycloalkyl, C _3- C ₁₀ heterocycloalkyl , C _5- C ₁₀ aryl, and C _5- C ₁₀ heteroaryl, which may or may not be substituted with one or more groups, particularly 1 to 4 groups.

As used herein, the term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic carbocycles, where the polycyclic ring is a fused ring, crosslinked ring, or spiro ring. possible. The carbon ring can have 3 to 10 carbon ring atoms. The intended carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

As used herein, the term "heterocycloalkyl" is a monocyclic or polycyclic (eg, bicyclic) saturated or partially unsaturated ring system with a total of 3 or more atoms. Contains (eg, 3-12, 4-10, 4-8, or 5-7), of which 1-5 (eg, 1, 2, 3, 4, or 5). Atoms mean a ring system selected from nitrogen, oxygen, and sulfur independently of each other. Non-limiting examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, and diaza. Cycloheptyl can be mentioned.

Unless otherwise specified, a cycloalkyl group or a heterocycloalkyl group may or may not be substituted with one or more, particularly 1 to 4 groups. Some of the intended substituents include halo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, Amino, -CO ₂ H, -CO ₂ C _1- C ₈ alkyl, -OCOC _1- C ₈ alkyl, C _3- C ₁₀ cycloalkyl, C _3- C ₁₀ heterocycloalkyl, C _5- C ₁₀ aryl, and C _5- C ₁₀ heteroaryl is included.

As used herein, the term "heteroaryl" contains 1 to 3 aromatic rings and contains 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur (eg, 1). Refers to a monocyclic or polycyclic ring system (eg, bicyclic) containing 1, 2, 3, or 4). In certain embodiments, the heteroaryl group has 5-20, 5-15, 5-10, or 5-7 ring atoms. Heteroaryl also refers to C- _10-14 bicyclic and tricyclic rings, where one ring is an aromatic ring and the other is a saturated, partially unsaturated, or aromatic ring. is there. Examples of heteroaryl groups include flanyl, imidazolyl, isothiazolyl, isooxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzoimidazolyl Oxazolyl, benzopyranyl, benzothiasiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, flopyridyl, imidazolidinyl, imidazolethiazolyl, indridinyl, indolyl, indazolyl, isobenzo Examples thereof include furanyl, isobenzothienyl, isoindyl, isoquinolinyl, isothiazolyl, naphthylidine, oxazolopyridinyl, phthalazinyl, pteridinyl, prynyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, chiazolinyl, thiadiazolopyrimidyl, and thienopyridyl. , Not limited to this. Unless otherwise specified, heteroaryl groups may or may not be substituted with one or more, particularly 1 to 4 or 1 or 2 substituents. The intended substituents are halo, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amino,-. _{CO 2 H, -CO 2 C 1} -C 8 alkyl, -OCOC ₁ -C _{8 alkyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10 heterocycloalkyl,} C 5 _{-C 10} aryl, and _{C 5} - C ₁₀ heteroaryl is included.

を指す。 As used herein, the term Boc is structural.

Point to.

を指す。 As used herein, the term Cbz is structural.

Point to.

を指す。 As used herein, the term Bn is structural.

Point to.

を指す。

Point to.

を指す。 As used herein, the term trityl is structural.

Point to.

を指す。 As used herein, the term tosyl is structural.

Point to.

を指す。 As used herein, the term Troc is structural.

Point to.

を指す。 As used herein, the term Teoc is structural.

Point to.

を指す。 As used herein, the term Alloc is structural.

Point to.

を指す。 As used herein, the term Fmoc is structural.

Point to.

Disclosure Compounds The present specification provides KRAS inhibitors having one structure of formulas IV, which are discussed in detail below.

The compounds disclosed herein include one or more atoms of the compounds disclosed herein having the same atomic number but having the same atomic mass or mass number, usually the mass or mass number of atoms found in nature. Includes all pharmaceutically acceptable isotope-labeled compounds that are substituted with atoms of different mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as each ^{2 H, 3 H, 11 C} , 13 C, 14 C , ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. These radiolabeled compounds characterize, for example, the site or mechanism of action, or their binding affinity for pharmacologically important sites of action, thereby assisting in determining or measuring the efficacy of the compound. Can be useful as. Certain isotope-labeled compounds of the present disclosure, such as those incorporating radioisotopes, are useful in the study of tissue distribution of drugs and / or substrates. In this purpose, tritium is radioactive isotope, i.e. ^{3 H,} and ^carbon-14, i.e. ^{14 C,} built is easy, and is particularly useful given that an immediate detection means.

Deuterium, i.e., the substitution with heavier isotopes such as ^{2 H,} can afford certain therapeutic advantages resulting from it is greater metabolic stability, for example, such as reduction of the extension or required dosage in vivo half-life It is preferable in some situations because it can be obtained.

Substitutions with positron-emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in determining substrate receptor occupancy in positron emission tomography (PET) examinations. Isotopic-labeled compounds of structure (I) are generally "prepared" below, either by prior art known to those skilled in the art or by using suitable isotopic-labeled reagents in place of the non-labeled reagents used so far. And can also be prepared by a process similar to the process described in "Examples".

The isotope-labeled compounds disclosed herein are generally examples of attachments that use a suitable isotope-labeled reagent, either by prior art known to those of skill in the art, or in place of the unlabeled reagents used so far. It can also be prepared by a process similar to that described in the scheme.

The particular compounds disclosed herein exist as stereoisomers (ie, isomers that differ only in the spatial arrangement of atoms), such as optical isomers and conformational isomers (or conformers). You can. The compounds disclosed herein include all stereoisomers, both pure individual stereoisomer preparations and their respective concentrated preparations, as well as racemic mixtures of such stereoisomers and those skilled in the art. Includes both individual diastereomers and enantiomers that can be separated according to known methods. In addition, the compounds disclosed herein include all tautomeric forms of the compound.

などの基は、回転が制限され得る。 Certain compounds disclosed herein have an impeded or significantly slower rotation around a single bond within the molecule as a result of stereoisomerism with the atropisomer, ie, other parts of the molecule. It may exist as a conformational stereoisomer that occurs in some cases. The compounds disclosed herein include all atropisomers, including pure individual atropisomer preparations, both enriched preparations, or non-specific mixtures thereof. Separation and isolation of isomer species may be possible if the rotational impairment around the single bond is large enough and if the interconversion between the conformations is slow enough. For example, although not limited to, the following ¹⁰ R units

Such groups can be restricted in rotation.

［式中、Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレンアミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^７はＨもしくはＣ_１〜３アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成する］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。 The present disclosure is based on formula (I).

[In the equation, E ¹ and E ² are independently N or CR ¹ , respectively.
R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is halo, C _1-6 alkyl, C _1-6 haloalkyl, OR', N (R') ₂ , C _2-3 alkynyl, C _2-3 alkynyl, C _0-3alkylene- C _3-8 cyclo Alkyne, C _0-3alkylene- C _2-7 heterocycloalkyl, C _{0-3alkylenearyl} , or C- _0-3alkylene heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or the two R'substituents are attached to each other with the nitrogen atom to which they are attached. Combine to form a 3- to 7-membered ring,
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6 haloalkyl, C 0 to 3} Alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3 alkylenearyl, or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} haloalkyl, C _1-6 alkyleneamine, C _0-6 alkyleneamide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _1-6 Alkylene-O-aryl, C _0-3alkylene- C (O) C _1-4 alkylene-OH, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl , C _0-3 alkylenearyl, or cyano, or R ⁵ and R ⁶ combine with each other with the atoms to which they bind to form a 4- to 6-membered ring, and R ⁷ is H or C _1-3. Alkyl, or R ⁷ and R ⁵ bond together with the atoms to which they bind to form a 4- to 6-membered ring]
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

の形態であり得る。 The compounds of formula I are of formula (IA), (IB), (IC), or (ID) :.

Can be in the form of.

［式中、Ｅ^１及びＥ^２はそれぞれ独立してＮまたはＣＲ^１であり、
ＪはＮ、ＮＲ^１０、またはＣＲ^１０であり、
ＭはＮ、ＮＲ^１３、またはＣＲ^１３であり、

は各原子にその通常の原子価を与えるよう必要に応じ単結合または二重結合であり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレンアミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜３アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、またはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９はそれぞれ独立してＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、シアノ、ニトロ、もしくはＣ_３〜６シクロアルキルであるか、またはＲ^８及びＲ^９はそれらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレンアリール、Ｃ_０〜３アルキレンヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレンアリール、Ｏ−Ｃ_０〜３アルキレンヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｏ−Ｃ_０〜３アルキレンアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレンアリール、ＮＨ−Ｃ_０〜３アルキレンヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレンアミンであり、
Ｒ^１３はＣ_１〜４アルキル、Ｃ_１〜３ハロアルキル、Ｃ_１〜３アルキレンアミン、及びＣ_３〜５シクロアルキル、またはその薬学的に許容される塩であるが、
（１）ＪがＮＲ^１０の場合、ＭはＮまたはＣＲ^１３であり、
（２）ＭがＮＲ^１３の場合、ＪはＮまたはＣＲ^１０であり、
（３）ＪがＣＲ^１０の場合、ＭはＮまたはＮＲ^１３であり、かつ
（４）ＭがＣＲ^１３の場合、ＪはＮまたはＮＲ^１０である］
の構造を有する化合物も提供する。 The present disclosure also includes formula (II).

[In the formula, E ¹ and E ² are independently N or CR ¹ , respectively.
J is N, NR ¹⁰ , or CR ¹⁰ .
M is N, NR ¹³ , or CR ¹³ .

Is a single or double bond as needed to give each atom its normal valence,
R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is halo, C _1-6 alkyl, C _1-6 haloalkyl, OR', N (R') ₂ , C _2-3 alkynyl, C _2-3 alkynyl, C _0-3alkylene- C _3-8 cyclo Alkyne, C _0-3alkylene- C _2-7 heterocycloalkyl, C _{0-3alkylenearyl} , or C- _0-3alkylene heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or the two R'substituents are attached to each other with the nitrogen atom to which they are attached. Combine to form a 3- to 7-membered ring,
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6 haloalkyl, C 0 to 3} Alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3 alkylenearyl, or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} haloalkyl, C _1-6 alkyleneamine, C _0-6 alkyleneamide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _1-6 Alkylene-O-aryl, C _0-3alkylene- C (O) C _1-4 alkylene-OH, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl , C _0-3 alkylenearyl, or cyano, or R ⁵ and R ⁶ combine with each other with the atoms to which they bind to form a 4- to 6-membered ring.
R ⁷ is H or C _1-3 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
R ⁸ and R ⁹ are independently H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, cyano, nitro, or C _3-6 cycloalkyl, respectively, or R ⁸ and R ⁹ are they. It can be bonded to each other together with the carbon atoms to be bonded to form a 3- to 6-membered ring.
R ¹⁰ is C _1-8 alkyl, C _0-3 alkylenearyl, C _0-3 alkylene heteroaryl, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl. , _{C 1 to 6} alkoxy, _{O-C 0 to 3} alkylenearyl, _{O-C 0 to 3} alkylene heteroaryl, _{O-C 0 to 3} alkylene _{-C 3 to 8} cycloalkyl, _{O-C 0 to 3} alkylenearyl, _{OC 0-3alkylene} -C _2-7 heterocycloalkyl, NH-C _1-8 alkyl, N (C _1-8 alkyl) ₂ , NH-C _0-3 alkylenearyl, NH-C _0-3 alkylene Heteroaryl, NH-C _0-3alkylene -C _3-8 cycloalkyl, NH-C _0-3alkylene -C _2-7 heterocycloalkyl, halo, cyano, or C _1-6 alkyleneamine.
R ¹³ is C _1-4 alkyl, C _1-3 haloalkyl, C _1-3 alkylene amine, and C _3-5 cycloalkyl, or pharmaceutically acceptable salts thereof.
(1) When J is NR ¹⁰ , M is N or CR ¹³ .
(2) When M is NR ¹³ , J is N or CR ¹⁰ .
(3) When J is CR ¹⁰ , M is N or NR ¹³ , and (4) When M is CR ¹³ , J is N or NR ^10. ]
Compounds having the above structure are also provided.

In various embodiments, J is NR ¹⁰ and M is CR ¹³ . In some embodiments, J is CR ¹⁰ and M is NR ¹³ . In some embodiments, J is CR ¹⁰ and M is N. In various embodiments, J is N and M is NR ¹³ . In some embodiments, J is N and M is CR ¹³ . Some specifically contemplated ^{R 13,} methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, trifluoromethyl, _CH 2 NH _2, and includes cyclopropyl. In some embodiments, J is NR ¹⁰ and M is N. In some embodiments, where Q is C = O and each of E ¹ and E ² is CR ¹ , (1) R ¹⁰ is C _1-3 alkylene aryl, C _1-3 alkylene heteroaryl, C _{0 to 3alkylene} -C _{3 to 8} cycloalkyl, C _{1 to 3} alkylene-C _{2 to 7} heterocycloalkyl, or halo, or (2) R ¹³ is C _{1 to 3} haloalkyl or C _{3 to 5} It is either cycloalkyl.

の形態であり得る。 The compounds of formula II are formulas (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), ( II-H), (II-J), (II-K), (II-L), (II-M), (II-N), (II-O), (II-P), or (II) -Q):

Can be in the form of.

［式中、各Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレンアミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜３アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
ＱはＣＲ^８Ｒ^９、Ｃ＝ＣＲ^８Ｒ^９、Ｃ＝Ｏ、Ｃ＝Ｓ、またはＣ＝ＮＲ^８であり、
Ｒ^８及びＲ^９の各々は互いに独立してＨ、Ｃ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、シアノ、ニトロ、もしくはＣ_３〜６シクロアルクリルであるか、またはＲ^８及びＲ^９は、それらが結合する炭素原子と共に互いに結合して３〜６員環を形成することができ、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレンアリール、Ｃ_０〜３アルキレンヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレンアリール、Ｏ−Ｃ_０〜３アルキレンヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレンアリール、ＮＨ−Ｃ_０〜３アルキレンヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレンアミンである］
の構造を有する化合物、またはその薬学的に許容される塩も提供する。 The present disclosure also includes formula (III) or formula (III'):

[In the formula, each R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , Cyano, or halo,
R ² is halo, C _1-6 alkyl, C _1-6 haloalkyl, OR', N (R') ₂ , C _2-3 alkynyl, C _2-3 alkynyl, C _0-3alkylene- C _3-8 cyclo Alkyne, C _0-3alkylene- C _2-7 heterocycloalkyl, C _{0-3alkylenearyl} , or C- _0-3alkylene heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or the two R'substituents are attached to each other with the nitrogen atom to which they are attached. Combine to form a 3- to 7-membered ring,
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6 haloalkyl, C 0 to 3} Alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3 alkylenearyl, or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} haloalkyl, C _1-6 alkyleneamine, C _0-6 alkyleneamide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _1-6 Alkylene-O-aryl, C _0-3alkylene- C (O) C _1-4 alkylene-OH, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl , C _0-3 alkylenearyl, or cyano, or R ⁵ and R ⁶ combine with each other with the atoms to which they are attached to form a 4- to 6-membered ring.
R ⁷ is H or C _1-3 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
Q is CR ⁸ R ⁹ , C = CR ⁸ R ⁹ , C = O, C = S, or C = NR ⁸ .
Each of R ⁸ and R ⁹ is independent of each other and is H, C _1-3 alkyl, hydroxy, C _1-3 alkoxy, cyano, nitro, or C _3-6 cycloalkryl, or R ⁸ and R ⁹ Can be bonded together with the carbon atoms to which they are attached to form a 3- to 6-membered ring, and R ¹⁰ is C _{1 to 8} alkyl, C _{0 to 3} alkylene aryl, C _{0 to 3} alkylene heteroaryl, C _0-3alkylene- C _3-8 cycloalkyl, C _0-3alkylene- C _2-7 heterocycloalkyl, C _1-6 alkoxy, C _1-6 alkoxy, _{OC 0-3} alkylenearyl, O- C _0-3 Alkoxy Heteroaryl, O-C _{0-3 Alkoxy} -C _3-8 Cycloalkyl, O-C _{0-3 Alkoxy} -C _2-7 Heterocycloalkyl, NH-C _{1-8 Alkoxy} , N (C _1-8 alkyl) ₂ , NH-C _0-3 alkylenearyl, NH-C _0-3 alkylene heteroaryl, NH-C _0-3 alkylene-C _3-8 cycloalkyl, NH-C _0-3 alkylene-C _2-7 heterocycloalkyl, halo, cyano, or C _1-6 alkyleneamines]
Also provided are compounds having the structure of, or pharmaceutically acceptable salts thereof.

の形態であり得る。 The compounds of formula III are of formula (III-A), (III-B), (III-C), or (III-D) :.

Can be in the form of.

の形態であり得る。 Compounds of formula III'are formula (III-A'), (III-B'), (III-C'), or (III-D') :.

Can be in the form of.

［式中、Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレンアミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜３アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^８はＣ_１〜３アルキル、ヒドロキシ、Ｃ_１〜３アルコキシ、ハロ、シアノ、ニトロ、Ｃ_３〜６シクロアルキル、またはＮＲ^１１Ｒ^１２であり、
Ｒ^１１及びＲ^１２はそれぞれ独立してＨ、Ｃ_１〜４アルキル、またはＣ_３〜５シクロアルキルであり、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレンアリール、Ｃ_０〜３アルキレンヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレンアリール、Ｏ−Ｃ_０〜３アルキレンヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ（Ｃ_１〜８アルキル）_２、ＮＨ−Ｃ_０〜３アルキレンアリール、ＮＨ−Ｃ_０〜３アルキレンヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレンアミンである］
の構造を有する化合物、またはその薬学的に許容される塩も提供する。いくつかの実施形態では、Ｅ^１及びＥ^２はそれぞれＣＲ^１であり、Ｒ^８はヒドロキシ、ハロ、ニトロ、またはＣ_３〜６シクロアルキルである。いくつかの実施形態では、Ｒ^８はメチルである。化合物は、式（ＩＶ−Ａ）、（ＩＶ’−Ａ）、（ＩＶ−Ｂ）、（ＩＶ’−Ｂ）、（ＩＶ−Ｃ）、（ＩＶ’−Ｃ）、（ＩＶ−Ｄ）、または（ＩＶ’−Ｄ）：

の構造を有し得る。 The present disclosure also includes formula (IV) or (IV'):

[In the formula, E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is halo, C _1-6 alkyl, C _1-6 haloalkyl, OR', N (R') ₂ , C _2-3 alkynyl, C _2-3 alkynyl, C _0-3alkylene- C _3-8 cyclo Alkyne, C _0-3alkylene- C _2-7 heterocycloalkyl, C _{0-3alkylenearyl} , or C- _0-3alkylene heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or the two R'substituents are attached to each other with the nitrogen atom to which they are attached. Combine to form a 3- to 7-membered ring,
R ³ is halo, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6 haloalkyl, C 0 to 3} Alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3 alkylenearyl, or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} haloalkyl, C _1-6 alkyleneamine, C _0-6 alkyleneamide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _1-6 Alkylene-O-aryl, C _0-3alkylene- C (O) C _1-4 alkylene-OH, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl , C _0-3 alkylenearyl, or cyano, or R ⁵ and R ⁶ combine with each other with the atoms to which they are attached to form a 4- to 6-membered ring.
R ⁷ is H or C _1-3 alkyl, or R ⁷ and R ⁵ bond with each other together with the atoms to which they bond to form a 4- to 6-membered ring.
R ⁸ is C _1-3 alkyl, hydroxy, C _1-3 alkoxy, halo, cyano, nitro, C _3-6 cycloalkyl, or NR ¹¹ R ¹² .
R ¹¹ and R ¹² are independently H, C _1-4 alkyl, or C _3-5 cycloalkyl, and R ¹⁰ is C _1-8 alkyl, C _0-3 alkylenearyl, C _0-3 alkylene, respectively. Heteroaryl, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _1-6 alkoxy, O-C _0-3 alkylenearyl, _{OC 0- 3-} alkylene heteroaryl, O-C _0-3alkylene -C _3-8 cycloalkyl, O-C _0-3alkylene -C _2-7 heterocycloalkyl, NH-C _1-8 alkyl, N (C _{1-8 alkyl)} 2, _NH-C 0~3 alkylene aryl, _NH-C 0~3 alkylene heteroaryl, _NH-C 0~3 alkylene _{-C 3 to 8} cycloalkyl, _NH-C 0~3 alkylene _{-C 2 to 7} Heterocycloalkyl, halo, cyano, or C _1-6 alkyleneamine]
Also provided are compounds having the structure of, or pharmaceutically acceptable salts thereof. In some embodiments, E ¹ and E ² are CR ¹ respectively and R ⁸ is hydroxy, halo, nitro, or C _3-6 cycloalkyl. In some embodiments, R ⁸ is methyl. The compounds are of formula (IV-A), (IV'-A), (IV-B), (IV'-B), (IV-C), (IV'-C), (IV-D), or (IV'-D):

Can have the structure of.

［式中、Ｅ^１及びＥ^２は、それぞれ独立してＣＲ^１またはＮであり、
Ｒ^１は独立してＨ、ヒドロキシ、Ｃ_１〜４アルキル、Ｃ_１〜４ハロアルキル、Ｃ_１〜４アルコキシ、ＮＨ−Ｃ_１〜４アルキル、Ｎ（Ｃ_１〜４アルキル）_２、シアノ、またはハロであり、
Ｒ^２はハロ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、ＯＲ’、Ｎ（Ｒ’）_２、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、またはＣ_０〜３アルキレンヘテロアリールであり、各Ｒ’は互いに独立してＨ、Ｃ_１〜６アルキル、Ｃ_１〜６ハロアルキル、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、もしくはヘテロアリールであるか、または２つのＲ’置換基はそれらが結合する窒素原子と共に互いに結合して３〜７員環を形成し、
Ｒ^３はハロ、Ｃ_１〜３アルキル、Ｃ_１〜２ハロアルキル、Ｃ_１〜３アルコキシ、Ｃ_３〜４シクロアルキル、Ｃ_２〜３アルケニル、Ｃ_２〜３アルキニル、アリール、またはヘテロアリールであり、
Ｒ^４は

であり、
環Ａは、単環式４〜７員環であるか、または二環式の架橋、縮合、もしくはスピロ式の６〜１１員環であり、
Ｌは結合、Ｃ_１〜６アルキレン、−Ｏ−Ｃ_０〜５アルキレン、−Ｓ−Ｃ_０〜５アルキレン、または−ＮＨ−Ｃ_０〜５アルキレンであり、かつＣ_２〜６アルキレン、−Ｏ−Ｃ_２〜５アルキレン、−Ｓ−Ｃ_２〜５アルキレン、及びＮＨ−Ｃ_２〜５アルキレンの場合、かかるアルキレン基の１個の炭素原子は任意選択でＯ、Ｓ、またはＮＨで置き換えることができ、
Ｒ^４’はＨ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリールであるか、または

から選択され、
Ｒ^５及びＲ^６はそれぞれ独立してＨ、ハロ、Ｃ_１〜８アルキル、Ｃ_２〜８アルキニル、Ｃ_１〜６アルキレン−Ｏ−Ｃ_１〜４アルキル、Ｃ_１〜６アルキレン−ＯＨ、Ｃ_１〜６ハロアルキル、Ｃ_１〜６アルキレンアミン、Ｃ_０〜６アルキレンアミド、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＨ、Ｃ_０〜３アルキレン−Ｃ（Ｏ）ＯＣ_１〜４アルキル、Ｃ_１〜６アルキレン−Ｏ−アリール、Ｃ_０〜３アルキレン−Ｃ（Ｏ）Ｃ_１〜４アルキレン−ＯＨ、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_０〜３アルキレンアリール、もしくはシアノであるか、またはＲ^５及びＲ^６はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、
Ｒ^７はＨもしくはＣ_１〜３アルキルであるか、またはＲ^７及びＲ^５はそれらが結合する原子と共に互いに結合して４〜６員環を形成し、かつ
Ｒ^１０はＣ_１〜８アルキル、Ｃ_０〜３アルキレンアリール、Ｃ_０〜３アルキレンヘテロアリール、Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、Ｃ_１〜６アルコキシ、Ｏ−Ｃ_０〜３アルキレンアリール、Ｏ−Ｃ_０〜３アルキレンヘテロアリール、Ｏ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、Ｏ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ＮＨ−Ｃ_１〜８アルキル、Ｎ−Ｃ_１〜８アルキル、ＮＨ−Ｃ_０〜３アルキレンアリール、ＮＨ−Ｃ_０〜３アルキレンヘテロアリール、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_３〜８シクロアルキル、ＮＨ−Ｃ_０〜３アルキレン−Ｃ_２〜７ヘテロシクロアルキル、ハロ、シアノ、またはＣ_１〜６アルキレンアミンである］
の構造を有する化合物、またはその薬学的に許容される塩を提供する。 The present specification also includes formula (V) :.

[In the formula, E ¹ and E ² are independently CR ¹ or N, respectively.
R ¹ is independently H, hydroxy, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, NH-C _1-4 alkyl, N (C _1-4 alkyl) ₂ , cyano, or halo. And
R ² is halo, C _1-6 alkyl, C _1-6 haloalkyl, OR', N (R') ₂ , C _2-3 alkynyl, C _2-3 alkynyl, C _0-3alkylene- C _3-8 cyclo Alkyne, C _0-3alkylene- C _2-7 heterocycloalkyl, C _{0-3alkylenearyl} , or C- _0-3alkylene heteroaryl, each _R'is independent of each other H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl, or the two R'substituents are attached to each other with the nitrogen atom to which they are attached. Combine to form a 3- to 7-membered ring,
R ³ is halo, C _1-3 alkyl, C _1-2 haloalkyl, C _1-3 alkoxy, C _3-4 cycloalkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, or heteroaryl.
R ⁴ is

And
Ring A is a monocyclic 4- to 7-membered ring, or a bicyclic cross-linked, condensed, or spiro-type 6 to 11-membered ring.
L is a bond, C _1-6 alkylene, -O-C _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene, -O- In the case of C _2-5 alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of such an alkylene group can optionally be replaced with O, S, or NH. ,
R ^{4 'is} _{H, C 1 to 8 alkyl, C 2 to 8 alkynyl, C 1 to 6} alkylene _{-O-C 1 to 4 alkyl, C 1 to 6} alkylene _{-OH, C 1 to 6 haloalkyl, C 0 to 3} Alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _0-3 alkylenearyl, or

Selected from
R ⁵ and R ⁶ are independently H, halo, C _1-8 alkyl, C _2-8 alkynyl, C _1-6 alkylene-OC _1-4 alkyl, C _1-6 alkylene-OH, C _{1 ~ 6} haloalkyl, C _1-6 alkyleneamine, C _0-6 alkyleneamide, C _0-3 alkylene-C (O) OH, C _0-3 alkylene-C (O) OC _1-4 alkyl, C _1-6 Alkylene-O-aryl, C _0-3alkylene- C (O) C _1-4 alkylene-OH, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl , C _0-3 alkylenearyl, or cyano, or R ⁵ and R ⁶ combine with each other with the atoms to which they are attached to form a 4- to 6-membered ring.
R ⁷ is H or C _1-3 alkyl, or R ⁷ and R ⁵ are bonded together with the atoms to which they are attached to form a 4- to 6-membered ring, and R ¹⁰ is C _{1 to 8} alkyl, C _0-3 alkylenearyl, C _0-3 alkylene heteroaryl, C _0-3 alkylene-C _3-8 cycloalkyl, C _0-3 alkylene-C _2-7 heterocycloalkyl, C _1-6 alkoxy, O- C _{0 to 3} alkylenearyl, _{O-C 0~3} alkylene heteroaryl, _{O-C 0~3} alkylene _{-C 3 to 8} cycloalkyl, _{O-C 0~3} alkylene _{-C 2 to 7} heterocycloalkyl, NH- C _1-8 alkyl, _{NC 1-8} alkyl, NH-C _0-3 alkylenearyl, NH-C _0-3 alkylene heteroaryl, NH-C _0-3 alkylene-C _3-8 cycloalkyl, NH- C _0-3 alkylene-C _2-7 heterocycloalkyl, halo, cyano, or C _1-6 alkylene amine]
Provided are a compound having the structure of, or a pharmaceutically acceptable salt thereof.

For compounds of formulas (II), (III), and (III'), in some embodiments Q is C = O. In some embodiments, Q is C = S. In some embodiments, Q is C = NR ⁸ . R ⁸ can be a C _1-2 alkyl, for example methyl.

Q can be CR ⁸ R ⁹ or C = CR ⁸ R ⁹ . R ⁸ and R ⁹ can be bonded together with the carbon atoms to which they are attached to form a 3- to 4-membered ring, such as a cyclopropyl ring. In some embodiments, R ⁸ is C _1-2 alkyl (eg, methyl) and R ⁹ is H.

が含まれる。Ｒ^１０は、オルト置換アリール、オルト置換ヘテロアリール、または２置換シクロヘキシル、例えば、

などを含むことができる。別の実施形態では、Ｒ^１０は、

を含むことができる。 For compounds of formulas (II), (III), (III'), (IV), (IV'), and (V), in various embodiments, R ¹⁰ is a C _1-4 alkyl, aryl, hetero. Aryl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _1-4 alkoxy, or aryloxy. In various embodiments, R ¹⁰ is C _1-8 alkyl, C _1-5 alkyl, or C _1-3 alkyl. In various embodiments, R ¹⁰ is C _0-3 alkylenearyl, C _0-1 alkylenearyl, or phenyl. In various embodiments, R ¹⁰ is a C _0-3 alkylene heteroaryl, or a C _{0 to 1} alkylene heteroaryl, which heteroaryl can be, for example, pyridyl. In various embodiments, R ¹⁰ is C _0-3alkylene- C _3-8 cycloalkyl, C _0-1 alkylene-C _3-8 cycloalkyl, or C _3-8 cycloalkyl, such cycloalkyl. For example, it can be cyclohexyl. In various embodiments, R ¹⁰ is C _0-3alkylene- C _3-8 heterocycloalkyl or C _0-1alkylene- C _3-8 heterocycloalkyl. In various embodiments, R ¹⁰ is a C- _0-6 alkyleneamine or a _C0-3 alkyleneamine or amine. Some specifically intended R ^10s include i-Pr, t-Bu, phenyl, benzyl, OCH ₃ , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Is included. R ¹⁰ is an ortho-substituted aryl, an ortho-substituted heteroaryl, or a di-substituted cyclohexyl, eg,

Etc. can be included. In another embodiment, the R ¹⁰ is

Can be included.

For all compounds:
R ¹ can be a small part. For example, R ¹ can be H, C _1-2 alkyl (eg, methyl), C _1-2 haloalkyl (eg, CF ₃ ), or halo (eg, F). The ^{R 1} contemplated several specifically, H, F, Me, include Cl, and CF _3.

が含まれる。いくつかの実施形態では、Ｒ^２は

である。 R ² is C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _{0 to 1} alkylene-C _{3 to 8} cycloalkyl, C _{3 to 6} cycloalkyl, C _{0 to 1} alkylene aryl (for example). , Aryl), or _C0-1 alkylene heteroaryl (eg, heteroaryl). Some More specifically contemplated R ² groups include phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, Included are quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl groups. Specific ^{R 2} in some other, Cl, Br, CF _3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, _{azetidine, OCH 3, OCH 2 CH 3} , phenyl,

Is included. In some embodiments, R ² is

Is.

R ³ can be halo (eg Cl, F), C _1-2 alkyl (eg methyl), or C _1-2 haloalkyl (eg CF ₃ ). Some specifically intended _{^{R 3, Cl, F, Me}} , CF 3, OMe, Et, C = CH 2, and includes cyclopropyl.

L can be a bond, C _1-6 alkylene, -OC _0-5 alkylene, -SC _0-5 alkylene, or -NH-C _0-5 alkylene, and C _2-6 alkylene,- In the case of _{OC 2-5} alkylene, -SC _2-5 alkylene, and NH-C _2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH. it can. For example, L is -CH _2- NH- when the carbon of the C ₂ alkylene group is replaced by NH, or -O-CH when the carbon of the OC ₃ alkylene group is replaced by O. It can be ₂ CH _2- O-. Other options of substituting C ₃ , C ₄ , C ₅ , or C ₆ alkylene with O, S, or NH are specifically intended. In some embodiments, L is C _1-2 alkylene, O, S, or NH. In some embodiments, L is a bond.

Ring A is a monocyclic 4- to 7-membered ring or a bicyclic, crosslinked, condensed, or spiro 6 to 11-membered ring. Some specifically intended rings include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, azetidinyl. , Spiroheptyl, spirooctyl, spirononyl, spirodecil, diazabicyclodecyl, diazabicyclononyl, diazabicyclooctyl, diazabicycloheptyl, hexahydropyrrolopyridyl, octahydropyrrolopyridyl, and octahydropyrrolopyrimidinyl. In various embodiments, ring A can include piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl. In some embodiments, ring A comprises piperidinyl. Ring A can be further substituted with 1-3 substituents. Some non-limiting examples of substitutions for ring A include alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxylic acid or ester, haloalkyl, alkylamine, C (O) NH ₂ , oxo, halo, cyano, and isocyano. Contains 1-3 substituents selected from.

の場合、環Ａは、例えば、

であり得る。具体的には、Ｒ^４が

の場合、環Ａは、例えば、

であり得る。 R ⁴

In the case of, the ring A is, for example,

Can be. More specifically, ^{R 4} is

In the case of, the ring A is, for example,

Can be.

の場合、より具体的には

であり得る。そのような実施形態では、環Ａは、例えば、

であり得る。 R ⁴

In the case of, more specifically

Can be. In such an embodiment, the ring A is, for example,

Can be.

が含まれる。 R ⁵ and R ⁶ are substituents on the acrylamide moiety of the KRAS inhibitor disclosed herein. In some embodiments, each of R ⁵ and R ⁶ is H. Some specifically contemplated ^{R 5} _{substituents, H, Br, Cl, F} , CN, CH 3, CF 3, CH 2 Br, CH 2 OH, CH 2 CH 2 OH, CH 2 OCH 2 Phenyl, cyclopropyl, phenyl, CH ₂ phenyl, CH ₂ OCH ₃ , CH ₂ N (CH ₃ ) ₂ , CH ₂ N (CH ₂ CH ₃ ) ₂ , CH ₂ CO ₂ H, CH ₂ CO ₂ CH ₃ , CH ₂ NHC (O) CH ₃ , CH ₂ C (O) NHCH ₃ , CH ₂ OC (O) CH ₃ , or

Is included.

が含まれる。 Some specifically contemplated ^{R 6} substituents, phenyl, _{cyclopropyl, CH 3, CF 3, CH} 2 CH 3, CH 2 NH 2, CH (CH 3) NH 2, CH (CH 3) ₂ NH ₂ , CH ₂ Cl, CH ₂ Br, CH ₂ OCH ₃ , CH ₂ O Phenyl, CH ₂ OH, CO ₂ H, CO ₂ CH ₂ CH ₃ , CH ₂ CO ₂ H, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ OH, CH ₂ CH ₂ N (CH ₃ ) ₂ , CH ₂ NHCH ₃ , C (O) NHCH ₃ , C (O) N (CH ₃ ) ₂ , CH ₂ C (O) NH phenyl, CH ₂ CHF ₂ , CH ₂ F, CHF ₂ , CH ₂ NHC (O) CH ₃ , CH ₂ NHCH ₂ CH ₂ OH, CH ₂ NHCH ₂ CO ₂ H, CH ₂ NH (CH ₃ ) CH ₂ CO ₂ CH ₃ , CH ₂ NHCH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OCH ₃ , CH ₂ NH (CH ₃ ) CH ₂ C (O) N (CH ₃ ) ₂ , CH ₂ NH (CH ₃ ) CH ₂ C (O) NHCH ₃ , CH ₂ CH ₂ CCH, CH ₂ NMe ₂ , CH ₂ NH (CH ₃ ) CH ₂ CH ₂ OH, CH ₂ NH (CH ₃ ) CH ₂ CH ₂ F, CH ₂ N ⁺ (CH ₃ ) ₃ , CH ₂ NHCH ₂ CHF ₂ , CH ₂ NHCH ₂ CH ₃ ,

Is included.

が含まれる。 R ⁵ and R ⁶ can be bonded together with the atoms to which they are attached to form a 4- to 6-membered ring, such as a 5- or 6-membered ring. In such a ring, R ⁵ and R ⁶ are combined.

Is included.

In most embodiments, R ⁷ is H. However, in some embodiments, R ⁷ is methyl. In other embodiments, R ⁷ and R ⁵ are combined to be -CH _2- or -C (O) CH _2- .

が含まれる。 Some specifically intended partial choices

Is included.

が含まれる。 Some R ⁴ substituents specifically intended,

Is included.

が含まれ得る。 Some R ^{4 'substituents} specifically intended,

Can be included.

から選択される構造を有する化合物を開示する。 In another embodiment, the invention

A compound having a structure selected from the above is disclosed.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

から選択される構造を有する化合物、またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を開示する。 In another embodiment, the invention

A compound having a structure selected from, or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer, or a pharmacologically an atropisomer thereof. Disclose the acceptable salts in.

In another embodiment, these compounds can be used as intermediates in the manufacturing process of the compounds of the present application.

In another embodiment, these compounds may be in pharmaceutically acceptable salt form.

In another embodiment, these compounds may be included in a pharmaceutical formulation comprising any one or more of the compounds and a pharmaceutically acceptable excipient.

In another embodiment, these compounds can be used in a method of inhibiting KRAS G12C in cells, comprising contacting the cells with any one compound of the compounds or a pharmaceutical formulation.

In another embodiment, these compounds can be used in a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of any of the compounds or compositions.

In another embodiment, the cancer is lung cancer, pancreatic cancer, or colorectal cancer.

In another embodiment, the cancer is lung cancer.

In another embodiment, the cancer is pancreatic cancer.

In another embodiment, the cancer is colorectal cancer.

In another embodiment, the method further comprises administering to a patient in need of it a therapeutically effective amount of an additional pharmaceutically active compound.

In another embodiment, another pharmaceutically active compound is carfilzomib.

In another embodiment, another pharmaceutically active compound is cytarabine.

In another embodiment, the invention comprises using one or more of the compounds for treating cancer in a subject.

In another embodiment, the invention comprises using one or more of the compounds in the preparation of a therapeutic agent for cancer.

In another embodiment, the cancer is a hematological malignancy.

In another embodiment, the invention comprises using one or more of the therapeutic compounds for cancer, wherein the cancer is a hematological malignancies.

The following Examples 1-11 are described using a classification system, where the first number refers to the method used for compound synthesis, the second number refers to the identification number, and the third. The numbers, as described, refer to the elution sequence of the compounds in the chromatographic separation step. In the absence of a third number, the compound is a single compound or a mixture of isomers. In the classification system used in Examples 12-53, the first number is the identification number and the second number, as described, refers to the elution sequence of the compounds in the chromatographic separation step. If there is no second number, the compound is a single compound or a mixture of isomers. In order to arrange the format, the serial numbers of the examples are interrupted, and the specific example numbers are intentionally omitted. A "-" means no change or no item in its associated box. Specific intended compounds include those listed in Table 1 and Table 1 (a).

Synthesis of Disclosure Compounds The compounds disclosed herein can be synthesized by a number of specific methods. The examples outlining a particular synthetic pathway, and the general schemes below, are intended to provide guidance to synthetic chemists with conventional skills, who are involved in solvents, concentrations, reagents, protections. It will be readily appreciated that the basis, sequence of synthesis steps, time, temperature, etc. can be adequately modified as needed within the skill and judgment of those skilled in the art.

方法１の合成：本明細書に開示する式（Ｉ）の化合物は、方法１に概説するように合成することができる。適切な芳香族酸またはヘテロ芳香族酸をステップ１のハロゲン化剤と反応させてハロゲン化芳香族酸またはハロゲン化ヘテロ芳香族酸を生成させる。その後、酸をステップ２のアミド化剤と反応させてアミド中間体を生成させる。その後、アミド中間体をステップ３の硫化剤と反応させてチオアミド中間体を生成させる。次に、チオアミド中間体をステップ４の酸化剤と反応させて図示のチアゾール環を形成させる。その後、ステップ５においてチアゾールのアミンを活性化剤を使用して脱離基に変換する。その後、脱離基を、ステップ６に示すように保護されたＲ^４基で置換する。その後、ステップ７において、適切なＲ^２（保護されている）試薬とチアゾール中間体のＸハロゲン化物とのクロスカップリング反応によって、Ｒ^２部分を導入する。次いで、ステップ８において、使用した保護基に応じ、適切な条件下でＲ^４基を脱保護した後、Ｒ^４基をアシル化して図示のようにアクリルアミド部分を導入し、最後にＲ^２を脱保護する。適切な保護基及び脱保護試薬は、例えば、Ｇｒｅｅｎｅ’ｓ Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓで考察されているように当業者に公知である。

Synthesis of Method 1: The compounds of formula (I) disclosed herein can be synthesized as outlined in Method 1. A suitable aromatic acid or heteroaromatic acid is reacted with the halogenating agent of step 1 to produce a halogenated aromatic acid or a halogenated heteroaromatic acid. The acid is then reacted with the amidating agent of step 2 to produce an amide intermediate. The amide intermediate is then reacted with the sulfurizing agent of step 3 to produce a thioamide intermediate. The thioamide intermediate is then reacted with the oxidizing agent of step 4 to form the thiazole ring shown. Then, in step 5, the amine of thiazole is converted to a leaving group using an activator. The leaving group is then replaced with ⁴ protected R groups as shown in step 6. Thereafter, in step 7, by a cross coupling reaction with X a halide of a suitable R ^{2 (protected)} reagent and thiazole intermediates to introduce the R ² moiety. Then, in step 8, depending on the protecting group used, followed by deprotection of the R ⁴ groups under appropriate conditions, to introduce acrylamide moiety as illustrated by acylating the R ⁴ group, and finally the R ² de Protect. Suitable protecting groups and deprotecting reagents are known to those of skill in the art, as discussed, for example, in Greene's Protective Groups in Organic Synthesis.

Intended halogenating agents include, but are not limited to, chlorine, bromine, N-chlorosuccinimide, and N-bromosuccinimide, optionally of catalysts such as iron or aluminum. In the presence. Synthetic chemists with normal skill will easily understand that the use of other halogenating agents and catalysts is possible.

As the intended amidating agent, N, N'-diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate, thionyl chloride, isobutyl chlorophosphate, diethyl cyanophosphonate, carbonyldiimidazole, and anhydrous polyphosphonate. Things can be mentioned, but not limited to this. Synthetic chemists with normal skill will easily understand that other amidating agents can be used.

Intended sulfidants include, but are not limited to, sulfur, diphosphorus pentasulfide, and Lawesson's reagent. Synthetic chemists with normal skill will easily understand that other sulfurizing agents can be used.

Intended oxidants include, but are not limited to, hydrogen peroxide, iodobenzene diacetate, t-butyl hydroperoxide, N-bromosuccinimide, and ammonium peroxodisulfate. Synthetic chemists with normal skill will easily understand that the use of other oxidizing agents is possible.

Intended activators include, but are not limited to, sodium nitrite and t-butyl nitrite. Synthetic chemists with normal workmanship will easily understand that other activators can be used.

Intended cross-coupling reactions include, but are not limited to, Suzuki coupling, Negishi coupling, Hiyama coupling, Kumada coupling, and Stille coupling. A chemist of ordinary skill will easily understand that a coupling as shown in Method 1 can be performed under a number of conditions.

方法２の合成：方法２では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。ステップ１のハロゲン化の後、ステップ２のカップリング反応で酸と反応させることにより保護されたＲ^４基を導入する。ステップ３においてオキソ基を硫化剤を使用してイオウに変換する。その後、ステップ４において酸化剤存在下でチアゾール環を形成させる。それ以降のステップ５〜８は、上記方法１のステップ７及び８と同様である。

Synthesis of Method 2: Method 2 provides an alternative method for forming the compounds of formula (I) disclosed herein. After the halogenation in step 1, ^four R groups protected by reacting with an acid in the coupling reaction in step 2 are introduced. In step 3, the oxo group is converted to sulfur using a sulfide agent. Then, in step 4, a thiazole ring is formed in the presence of an oxidizing agent. Subsequent steps 5 to 8 are the same as steps 7 and 8 of the above method 1.

方法３の合成：方法３では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。ステップ１においてイソチアゾール中間体のＲ^４基の脱保護及びアシル化を行い、アクリルアミド部分を導入する。その後、ステップ２において、適切なＲ^２（保護されている）試薬とイソチアゾール中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^２部分を導入する。最後に、ステップ３において、Ｒ^２基を脱保護する。

Synthesis of Method 3: Method 3 provides an alternative method for forming the compounds of formula (I) disclosed herein. Deprotection and acylation of R ⁴ groups isothiazole intermediate in Step 1, to introduce the acrylamide moiety. Then, in step 2, to introduce the R ² moiety by a cross coupling reaction with X a halide of a suitable R ^{2 (protected)} reagent isothiazole intermediates. Finally, in step 3, ^two R groups are deprotected.

方法４の合成：方法４では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。ステップ１に示すように、イソチアゾール中間体の脱離基を保護されたＲ^４基で置換した後、ステップ２においてＲ^４基中間体の脱保護及びアシル化を行い、アクリルアミド部分を導入する。方法１のようにステップ３においてクロスカップリング反応によりＲ^２部分を導入し、ステップ４においてＲ^２基を脱保護する。

Synthesis of Method 4: Method 4 provides an alternative method for forming the compounds of formula (I) disclosed herein. As shown in step 1, it was replaced with R ⁴ group which is protected with a leaving group of the isothiazole intermediate. Deprotection and acylation of R ⁴ group intermediate in step 2, to introduce the acrylamide moiety. Introducing R ² moiety in step 3 as in the method 1 the cross-coupling reaction, the group R ² is deprotected in step 4.

方法５の合成：方法５では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。この代替方法では、ステップ１に示す芳香族またはヘテロ芳香族のアミド中間体のＸハロゲン化物とのクロスカップリングによって最初にＲ^２部分を導入する。その後、ステップ２においてアミド中間体を硫化剤と反応させてチオアミド中間体を生成させる。ステップ３においてこの中間体を酸化させることによりイソチアゾール環が提供される。その後、ステップ４においてアミン基を脱離基に変換し、続いてステップ５において、保護されたＲ^４基で置換する。最後に、ステップ６において、Ｒ^４基を脱保護し、アシル化剤と反応させた後、Ｒ^２基を脱保護する。

Synthesis of Method 5: Method 5 provides an alternative method for forming the compounds of formula (I) disclosed herein. In this alternative method, initially to introduce the R ² moiety by cross-coupling between the X halides of aromatic or heteroaromatic amide intermediates shown in step 1. Then, in step 2, the amide intermediate is reacted with a sulfide agent to produce a thioamide intermediate. The isothiazole ring is provided by oxidizing this intermediate in step 3. Then, to convert the amine group to a leaving group in step 4, Subsequently, in Step 5, replacing a protected R ⁴ group. Finally, in Step 6, deprotection of the R ⁴ group, is reacted with a acylating agent, deprotecting the R ² groups.

方法６の合成：方法６では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。この代替方法では、イソチアゾール中間体をメタル化剤と反応させ、Ｘハロゲン化物を活性化させる。その後、活性化中間体と適切なＲ^２（保護されている）試薬とを反応させてＲ^２基を導入する。最終ステップにおいて、Ｒ^４基の脱保護及びアシル化を行い、アクリルアミド部分を導入する。

Synthesis of Method 6: Method 6 provides an alternative method for forming the compounds of formula (I) disclosed herein. In this alternative method, the isothiazole intermediate is reacted with a metalizing agent to activate the X halide. The activation intermediate is then reacted with the appropriate R ² (protected) reagent to introduce the R ² group. In the final step. Deprotection and acylation of R ⁴ groups, to introduce the acrylamide moiety.

Intended metallizing agents include, but are not limited to, bis (pinacolato) diboron, magnesium, zinc, hexamethyldistannan, and n-butyllithium. Synthetic chemists with normal skill will easily understand that the use of other metallizers and catalysts is possible.

方法７の合成：方法７では、本明細書に開示する式（Ｉ）の化合物を形成させるための代替方法を提供する。ステップ１に示す芳香族酸またはヘテロ芳香族酸中間体のＸハロゲン化物とのクロスカップリングによって最初にＲ^２部分を導入する。その後、ステップ２においてアミド化剤存在下、酸部分を適切なＲ^４（保護されている）試薬と反応させる。その後、ステップ３において酸誘導体のカルボニル基を硫化剤を使用してチオカルボニル基に変換する。その後、ステップ４においてチオ酸誘導体を酸化剤と反応させてイソチアゾール中間体を生成させる。最後に、Ｒ^４基の脱保護及びアシル化を行ってアクリルアミド部分を導入し、Ｒ^２基を脱保護する。

Synthesis of Method 7: Method 7 provides an alternative method for forming the compounds of formula (I) disclosed herein. First to introduce R ² parts by cross-coupling between the X halides aromatic acid or heteroaromatic aromatic acid intermediates shown in step 1. Thereafter, amidation agent presence in step 2, reacting the acid moiety with the appropriate R ^{4 (protected)} reagent. Then, in step 3, the carbonyl group of the acid derivative is converted to a thiocarbonyl group using a sulfurizing agent. Then, in step 4, the thioic acid derivative is reacted with an oxidizing agent to produce an isothiazole intermediate. Finally, introducing the acrylamide moiety by performing deprotection and acylation of the R ⁴ group, deprotecting the R ² groups.

方法８の合成：本明細書に開示する式（ＩＩ）の化合物は、方法８に概説するように合成することができる。ステップ１において適切な芳香族酸またはヘテロ芳香族酸をアミド化剤と反応させ、第一級アミド中間体を生成させる。その後、アミドをイソシアナート形成試薬及びＲ^１０置換アミンと反応させ、尿素中間体を生成させる。意図されるイソシアナート形成剤には、塩化オキサリル、塩化チオニル、及びオキシ塩化リンが含まれる。その後、ステップ３において尿素中間体を環化剤と反応させ、図示のキナゾリンジオン環を形成させる。意図される環化剤としては、塩基、例えば、カリウムヘキサメチルジシラジド、カリウムｔｅｒｔ−ブトキシド、水素化ナトリウム、及びホスファゼンなどの塩基が挙げられるが、これに限定されるものではない。その後、ステップ４において適切なＲ^２（保護されている）試薬とキナゾリンジオン中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^２部分を導入する。その後、ステップ５においてキナゾリンジオンのオキソ基を活性化剤を使用して脱離基に変換する。意図される活性化剤としては、塩化チオニル、トリフリン酸無水物、オキシ塩化リン、及び五塩化リンが挙げられるが、これに限定されるものではない。その後、ステップ６に示すように、脱離基を保護されたＲ^４基で置換して置換キナゾリノンを生成させる。ステップ７〜９において示される、それ以降の脱保護−アシル化−脱保護の順序は、方法１のステップ８と同様である。

Synthesis of Method 8: The compounds of formula (II) disclosed herein can be synthesized as outlined in Method 8. In step 1, the appropriate aromatic or heteroaromatic acid is reacted with the amidating agent to produce a primary amide intermediate. Thereafter, the amide is reacted with an isocyanate-forming reagent and R ¹⁰ substituted amine, to form a urea intermediate. The intended isocyanate-forming agents include oxalyl chloride, thionyl chloride, and phosphorus oxychloride. Then, in step 3, the urea intermediate is reacted with the cyclizing agent to form the illustrated quinazoline dione ring. Intended cyclizers include, but are not limited to, bases such as, but are not limited to, bases such as potassium hexmethyldisilazide, potassium tert-butoxide, sodium hydride, and phosphazene. The R ² moiety is then introduced in step 4 by a cross-coupling reaction between the appropriate R ² (protected) reagent and the X-halide of the quinazoline dione intermediate. Then, in step 5, the oxo group of quinazoline dione is converted to a leaving group using an activator. Intended activators include, but are not limited to, thionyl chloride, trifuric acid anhydride, phosphorus oxychloride, and phosphorus pentachloride. Thereafter, as shown in Step 6, to produce a substituted quinazolinone substituted with R ⁴ group which is protected with a leaving group. The subsequent deprotection-acyllation-deprotection sequence shown in steps 7-9 is similar to step 8 of method 1.

方法９の合成：方法９では、本明細書に開示する式（ＩＩ）の化合物を形成させるための代替方法を提供する。ステップ１においてキナゾリンジオンのオキソ基を脱離基に変換する。ステップ２では、Ｒ^４（保護されている）基の導入、Ｒ^４基の脱保護、及び遊離Ｒ^４基のアシル化を行う。ステップ３において、適切なＲ^２（保護されている）試薬とキナゾリンジオン中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^２基を導入する。最後に、Ｒ^２基を脱保護する。

Synthesis of Method 9: Method 9 provides an alternative method for forming the compounds of formula (II) disclosed herein. In step 1, the oxo group of quinazoline dione is converted to a leaving group. In step 2, the introduction of R ⁴ (protected) groups, the deprotection of R ⁴ groups, and the acylation of free R ⁴ groups are performed. In step 3, R ² groups are introduced by a cross-coupling reaction between the appropriate R ² (protected) reagent and the X-halide of the quinazoline dione intermediate. Finally, the ^two R groups are deprotected.

方法１０の合成：本明細書に開示する式（Ｖ）の化合物は、方法１０に概説するように合成することができる。ステップ１に示すように適切な無水物をヒドラジンと反応させてフタラジンジオン環を形成させる。ステップ２において適切なＲ^２試薬とキナゾリンジオン中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^２部分を導入する。その後、ステップ３においてＲ^２基を保護する。フタラジンジオン環を２回ハロゲン化させる。意図されるハロゲン化剤には、塩化チオニル、オキシ塩化リン、及び塩化オキサリルが含まれる。その後、ステップ５に示すように、ハロゲン基の１つを保護されたＲ^４基で置換して置換フタラジン環を形成させる。次いで、ステップ６及び７において、使用した保護基に応じ、適切な条件下でＲ^４基を脱保護し、次いで遊離Ｒ^４基をアシル化してアクリルアミド部分を導入する。ステップ８においてＲ^２を脱保護する。最後に、ステップ９において適切なＲ^１０試薬とフタラジン中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^１０部分を導入する。

Synthesis of Method 10: Compounds of formula (V) disclosed herein can be synthesized as outlined in Method 10. As shown in step 1, the appropriate anhydride is reacted with hydrazine to form a phthalazinedione ring. Introducing R ² moiety by a cross coupling reaction with X a halide of a suitable R ² reagent quinazolinedione intermediate in step 2. Then, in step 3, ^two R groups are protected. The phthalazindione ring is halogenated twice. Intended halogenating agents include thionyl chloride, phosphorus oxychloride, and oxalyl chloride. Thereafter, as shown in Step 5, to form a substituted phthalazine ring substituted with R ⁴ group protected with one of the halogen group. Then, in Step 6 and 7, depending on the protecting group used, deprotection of the R ⁴ groups under suitable conditions, and then the free R ⁴ group is acylated to introduce the acrylamide moiety. Deprotect R ² in step 8. Finally, in step 9, the R ¹⁰ moiety is introduced by a cross-coupling reaction of the appropriate R ¹⁰ reagent with the X halide of the phthalazine intermediate.

方法１１の合成：方法１１では、本明細書に開示する式（ＩＩ）の化合物を形成させるための代替方法を提供する。ステップ１においてキナゾリンジオンのオキソ基を脱離基に変換する。ステップ２においてＲ^４（保護されている）基を導入する。ステップ３において、適切なＲ^２（保護されている）試薬とキナゾリンジオン中間体のＸハロゲン化物とのクロスカップリング反応によってＲ^２基を導入する。最後に、Ｒ^４基を脱保護し、その後ステップ４及び５においてアシル化する。

Synthesis of Method 11: Method 11 provides an alternative method for forming the compounds of formula (II) disclosed herein. In step 1, the oxo group of quinazoline dione is converted to a leaving group. Introducing R ^{4 (protected)} group in step 2. In step 3, R ² groups are introduced by a cross-coupling reaction between the appropriate R ² (protected) reagent and the X-halide of the quinazoline dione intermediate. Finally, deprotection of R ⁴ groups, acylated in subsequent steps 4 and 5.

Pharmaceutical Compositions, Administrations, and Routes of Administration The present specification also provides pharmaceutical compositions containing the compounds disclosed herein together with pharmaceutically acceptable excipients such as diluents or carriers. Suitable compounds and pharmaceutical compositions for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. Administration of the compound is detailed below.

Suitable pharmaceutical formulations can be determined by one of ordinary skill in the art depending on the route of administration and the desired dose. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). The formulation can affect the physical condition, stability, in vivo release rate and in vivo clearance rate of the administered drug. Suitable doses may be calculated according to body weight, body surface area or organ size, depending on the route of administration. Further refinement of the calculations required to determine the appropriate therapeutic dose is available without undue experimentation, in particular through dose information and the evaluation methods disclosed herein and clinical trials in animals or humans. Performed routinely by one of ordinary skill in the art in the light of pharmacokinetic data.

The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" refers to molecular species and compositions that do not cause adverse reactions, allergic reactions, or other adverse reactions when administered to animals or humans. Point to. As used herein, "pharmaceutically acceptable" includes all solvents, dispersion media, coating agents, antibacterial and antifungal agents, tonicity agents, absorption retarders and the like. The use of such excipients for pharmaceutically active substances is well known in the art. Any conventional medium or agent is intended to be used in a Therapeutic composition unless it is incompatible with the Therapeutic composition. Auxiliary active compounds can also be incorporated into the composition. In an exemplary embodiment, the formulation is corn syrup solid, high oleic acid saflower oil, palm oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (embroidery), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-aspartin monohydrate, L-serine, potassium citrate, L- Threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine = dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m -Inositol, Iron Sulfate, Ascorbic Palmitate, Zinc Sulfate, L-Carnitine, Alpha-Tocopheryl Acetate, Sodium Chloride, Niacinamide, Mixed Tocopherol, Calcium Pantothenate, Copper Sulfate, Thiamine Chloride Hydrochloride, Vitamin A Palmitate, It may contain manganese sulphate, riboflavin, pyridoxin hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamine.

The compound may be present in the pharmaceutical composition as a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salts" include, for example, base-added salts and acid-added salts.

Pharmaceutically acceptable base addition salts may be formed using metals or amines such as alkali metals and alkaline earth metals or organic amines. The pharmaceutically acceptable salt of the compound may also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those of skill in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium, ferric and the like. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N, N'-dibenzylethylenediamine, chloroprocine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and prokine.

Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, formic acid, acetic acid, citrate, oxalic acid, tartaric acid, or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or In addition to phosphoric acid, organic carboxylic acids, sulfonic acids, acids with sulfo or phospho groups or N-substituted sulfamic acids such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleine Acids, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citrate, benzoic acid, silicic acid, mandelic acid, salicylic acid, 4-amino Such as salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, as well as 20 alpha amino acids used in natural protein synthesis, such as glutamate or aspartic acid. In addition to amino acids, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene Combined with -1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose-6-phosphate, N-cyclohexylsulfamic acid (with cyclamate formation), or other acidic organic compounds, ascorbic acid, etc. Is included.

Pharmaceutical compositions containing the compounds disclosed herein can be prepared by conventional methods such as conventional mixing, dissolution, granulation, dragee production, micronization, emulsification, encapsulation, capture, or lyophilization. It can be manufactured by the process. The appropriate formulation depends on the route of administration of choice.

For oral administration, suitable compositions can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients such as carriers well known in the art. With such excipients and carriers, it is possible to formulate the compound of the present application for oral ingestion of patients to be treated as tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions and the like. Become. For oral pharmaceutical preparations, the compounds disclosed herein are added using solid excipients, the resulting mixture is optionally ground, and if necessary, suitable auxiliaries are added before processing the granule mixture. It can be prepared by obtaining a tablet or a sugar-coated tablet core. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can be added if desired. A wide variety of formulations are known as pharmaceutically acceptable raw materials, such as binders for various formulations (eg, natural or synthetic polymers), lubricants, surfactants, sweeteners. And may be flavoring agents, coating materials, preservatives, pigments, thickeners, adjuvants, antibacterial agents, antioxidants and carriers.

When orally administered in therapeutically effective amounts of the disclosed compounds herein, the composition is typically in solid form (eg, tablets, capsules, pills, powders, or lozenges) or in liquid form (eg, aqueous). Suspensions, solutions, elixyl agents, or syrup agents).

When administered in tablet form, the composition can further contain functional solids and / or solid carriers such as gelatin or adjuvants. Tablets, capsules, and powders can contain from about 1 to about 95% compound, preferably from about 15 to about 90% compound.

When administered in liquid or suspension form, functional liquids and / or liquid carriers such as water, petroleum, or animal-derived or plant-derived oils can be added. The composition in liquid form can further contain saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition comprises from about 0.5 to about 90% by weight of the disclosed compounds herein, preferably from about 1 to about 50% of the disclosed compounds herein. can do. In one intended embodiment, the liquid carrier is either non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be delivered as an instantly soluble solid preparation that is dissolved or suspended immediately prior to administration.

When a therapeutically effective amount of the disclosed compounds herein is administered by intravenous, dermal or subcutaneous injection, the composition is in a pyrogen-free, parenterally acceptable aqueous form. The preparation of such parenterally acceptable solutions should be considered with respect to pH, isotonicity, stability, etc., but these are within the skill of those skilled in the art. Preferred compositions for intravenous, dermal, or subcutaneous injection typically contain isotonic vehicles in addition to the compounds disclosed herein. Such compositions may be prepared for administration as an aqueous solution of a free base or pharmacologically acceptable salt, preferably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol and mixtures thereof, and in oils. Under normal storage and use conditions, these preparations can optionally contain preservatives to prevent the growth of microorganisms.

Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for preparing sterile injectables, suspensions, or dispersions at the time of use. In all embodiments, such form must be sterile and must be fluid enough to easily pass through the needle. It must be stable under manufacturing and storage conditions and must be resistant to the contaminants of microorganisms such as bacteria and fungi by optionally including preservatives. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), a suitable mixture thereof, and vegetable oil. In one intended embodiment, the carrier is non-aqueous or substantially non-aqueous. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required compound particle size in the dispersion embodiments, and using surfactants. Prevention of microbial action can be provided by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many embodiments, it may be preferable to include an isotonic agent, such as sugar or sodium chloride. Sustained absorption of the injectable composition can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

Sterilized injections are prepared by incorporating the active compound in the required amount, optionally with a variety of other listed ingredients, in a suitable solvent and then filter sterilization. Generally, the dispersion is prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basal dispersion medium and other required raw materials listed above. In embodiments of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and lyophilization to give powders with the addition of the active ingredient and any additional desired ingredients obtained from the previously sterile filtered solution. It is a law.

Releasing or sustained-release preparations may be prepared to achieve controlled release of active compounds that come into contact with body fluids in the gastrointestinal tract and to ensure substantially constant and effective levels of active compounds in plasma. .. For example, release can be controlled by one or more of elution, diffusion, and ion exchange. In addition, release formulations can enhance absorption by saturated or restrictive pathways in the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix of biodegradable polymers, water-soluble polymers or mixtures thereof, and optionally suitable surfactants. In this case, embedding means embedding fine particles in the polymer matrix. Controlled release formulations can also be obtained by encapsulation of dispersed microparticles or emulsified microdrops with known dispersion or emulsion coating techniques.

For administration by inhalation, the compounds of the invention are conveniently delivered in the form of aerosol sprays presented from pressure packs or nebulizers using suitable propellants. In embodiments of pressurized aerosols, the unit of administration may be determined by providing a valve for delivering the quantification. Capsules and cartridges (eg made of gelatin) for use in inhalers or inhalers can be formulated with a powder mixture of compounds and a suitable powder base such as lactose or starch.

The compounds disclosed herein can be formulated for parenteral administration by injection (eg, bolus injection or continuous infusion). Injectable formulations may be presented in unit dosage forms (eg, in ampoules or multi-dose containers) with the addition of preservatives. Compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and are substances for formulation such as suspending agents, stabilizers, and / or dispersants. Can be contained.

Pharmaceutical formulations for parenteral administration include aqueous compounds in water-soluble forms. In addition, compound suspensions can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension may contain a suitable stabilizer or agent that increases the solubility of the compound, allowing the preparation of highly concentrated solutions. Alternatively, the included composition may be in powder form for pre-use use with a suitable vehicle (eg, pyrogen-free sterile water).

The compounds disclosed herein can also be formulated into rectal compositions such as suppositories or stagnant enemas (eg, containing conventional suppository bases). In addition to the formulations described above, compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by transplantation (eg, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compound is formulated with a suitable polymeric or hydrophobic substance (eg, as an emulsion in an acceptable oil) or ion exchange resin, or as a slightly insoluble derivative, eg, slightly insoluble. Can be formulated as a salt of.

In particular, the compounds disclosed herein are in the form of tablets containing excipients such as starch or lactose, or capsules or ovules (mixtures or singles with excipients), or flavoring or coloring agents. It can be orally, buccal, or sublingually administered in the form of an excipient or suspension containing. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspensions. The compounds can also be injected parenterally, eg, intravenously, intramuscularly, subcutaneously, or intracoronary. For parenteral administration, the compound is best used in the form of a sterile aqueous solution that can contain other substances, such as salts, or sugar alcohols such as mannitol or glucose, to make the solution isotonic with blood. Is.

For animals, the disclosed compounds herein are administered as a suitablely acceptable formulation according to conventional veterinary procedures. The veterinarian can easily determine the optimal administration regimen and route of administration for an individual animal.

In some embodiments, the compounds disclosed herein are used alone or in combination with other agents or traditional interventions in the treatment of such diseases for KRAS-related disorders. All components required for treatment may be packaged in a kit. Specifically, the invention provides a kit for use in therapeutic interventions for diseases, including a complete package of pharmaceuticals, which include the compounds and buffers disclosed herein and the deliveryable form preparation of said pharmaceuticals. Included with other components of the drug, and / or delivery device for such drug, and / or any drug used in combination therapy with the compounds disclosed herein, and / or drug. Includes instructions for treating the disease. Instructions refer to data sources on any tangible medium, such as printed matter, or computer-readable magnetic or optical media, or remote computer data sources such as worldwide web pages accessible via the Internet. It may be fixed to a book or the like.

"Therapeutically effective amount" means an effective amount for treating or preventing the onset of the subject to be treated, or for alleviating existing symptoms. The determination of an effective amount is well within the ability of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. In general, "therapeutically effective dose" refers to the amount of compound that results in the achievement of the desired effect. For example, in a preferred embodiment, therapeutically effective amounts of the disclosed compounds herein increase KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30 as compared to controls. %, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% Refers to a decline.

The amount of compound administered includes the subject to be treated, the subject's age, health, gender, and weight, the type of combination treatment (if received), the severity of the illness, the nature of the desired effect, the method of treatment and It may depend on the frequency as well as the judgment of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen tension. However, the most preferred dose can be tailored to the individual subject, which can be understood and determined by one of ordinary skill in the art without undue experimentation. In this case, the standard dose is typically adjusted (eg, dose reduction if the patient is underweight).

Determining the optimum range of effective amounts of a compound is within the skill of one of ordinary skill in the art, although individual needs vary. For example, when administered to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, typical doses of the compounds of the invention are from about 0.05 mg / kg / day to about 50 mg / kg. / Day, eg, at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0 It can be .5 mg / kg, preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, for example about 2.5 mg / day ( It can range from 0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dose of the compound is from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg. / Kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / Day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day , About 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about It can be from 10 mg / day to about 100 mg / day, from about 3 mg / day to about 10 mg / day, or from about 100 mg / day to about 250 mg / day. Such doses may be administered in single doses or in divided doses.

Methods Using KRAS G12C Inhibitors The present disclosure provides methods of inhibiting RAS-mediated cellular signaling, including contacting cells with an effective amount of one or more of the disclosed compounds herein. Inhibition of RAS-mediated signaling can be evaluated and demonstrated by a wide variety of methods known in the art. Non-limiting examples include (a) a decrease in GTPase activity of RAS, (b) a decrease in GTP binding affinity or an increase in GDP binding affinity, and (c) an increase in GTP Koff or Showing a decrease in GDP Koff, (d) a decrease in signaling molecule levels downstream of the RAS pathway, such as a decrease in levels of pMEK, pERK, or pAKT, and / or (e) a decrease in RAS complex. Includes showing reduced binding to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be used to determine one or more of the above.

The disclosure also provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat pathological conditions involving, but not limited to, mutations in G12C KRAS, HRAS or NRAS (eg, cancer). To do.

In some embodiments, a method for the treatment of cancer is provided, the method comprising an effective amount of any of the above-mentioned pharmaceutical compositions comprising the disclosed compounds herein, in a subject requiring it. Including administration. In some embodiments, the cancer is induced by a G12C mutation in KRAS, HRAS or NRAS. In various embodiments, the cancer is pancreatic cancer, colon cancer or lung cancer. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and bile duct cancer.

In some embodiments, the disclosure provides a method of treating a disorder of a subject in need of treatment of the disorder, wherein the method comprises whether the subject has a G12C variant of KRAS, HRAS or NRAS. If the subject is determined to have a G12C mutation in KRAS, HRAS or NRAS, then the subject is given at least one therapeutically effective dose of the disclosed compound herein or a pharmaceutically acceptable salt thereof. Includes administration of.

The disclosed compounds have the ability to inhibit tumor metastasis because they inhibit scaffold-independent cell proliferation. Thus, in another embodiment, the disclosure provides a method of inhibiting tumor metastasis, which method comprises administering an effective amount of the disclosed compound herein.

G12C mutations in KRAS, HRAS or NRAS have also been identified in hematological malignancies (eg, cancers that affect blood, bone marrow and / or lymph nodes). Therefore, certain embodiments are intended to administer the disclosed compound (eg, in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the compounds disclosed in the present application are acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML). ), Acute myelogenous leukemia (AMOL) and / or can be used to treat other diseases such as leukemia. In other embodiments, the compounds are useful in the treatment of lymphomas, such as all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma. In various embodiments, the compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenström macroglobulinemia.

To determine if a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation, evaluate the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, evaluate the amino acid sequence of the KRAS, HRAS or NRAS protein. This can be done by assessing the characteristics of the putative KRAS, HRAS or NRAS mutant proteins. Sequences of wild-type human KRAS, HRAS or NRAS are known in the art (eg, accession number NP203524).

Methods of detecting mutations in KRAS, HRAS or NRAS nucleotide sequences are known to those of skill in the art. These methods include the polymerase chain reaction-restricted enzyme fragment length polymorphism (PCR-RFLP) method, the polymerase chain reaction-single nucleotide polymorphism (PCR-SCSP) method, real-time PCR method, and PCR sequencing. Mutant allergen-specific PCR amplification (MASA), direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation, hybridization, TaqMan assay, SNP genotyping assay, high-resolution melting curve analysis and microarray analysis However, it is not limited to this. In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR. Real-time PCR uses fluorescent probes specific for G12C mutations in KRAS, HRAS or NRAS. If mutations are present, the probe binds and fluorescence is detected. In some embodiments, direct sequencing methods are used to identify specific regions of the KRAS, HRAS or NRAS gene (eg, exon 2 and / or exon 3) to identify G12C mutations in KRAS, HRAS or NRAS. This technique identifies all possible mutations in the region where the sequencing was performed.

Methods of detecting mutations in the KRAS, HRAS or NRAS proteins are known to those of skill in the art. These methods include detection of KRAS, HRAS or NRAS variants using mutant protein-specific binding agents (eg, antibodies), protein electrophoresis and Western blotting, and direct peptide sequencing. , Not limited to this.

A wide variety of samples can be used in the method of determining whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation. In some embodiments, a sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into cell lysates. In some embodiments, the sample is processed into DNA or RNA.

The disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, which method comprises administering to the mammal a therapeutically effective amount of the disclosed compound herein, or a pharmaceutically acceptable salt thereof. .. In some embodiments, the method comprises acute myeloid leukemia, adolescent cancer, pediatric corticolytic cancer, AIDS-related cancers (eg, lymphoma and capoic sarcoma), anal cancer, worm drop cancer, stellate cancer. Celloma, atypical malformation, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, barkit lymphoma, cartinoid tumor, atypical malformation, Fetal tumor, embryonic cell tumor, primary lymphoma, cervical cancer, childhood cancer, spinal tumor, heart tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon Cancer, colon cancer, cranopharyngeal tumor, cutaneous T-cell lymphoma, extrahepatic bile duct intraepithelial cancer (DCIS), fetal tumor, CNS cancer, endometrial cancer, coat cell tumor, esophageal cancer, nasal cavity Neuroblastoma, Ewing sarcoma, extracranial embryonic cell tumor, extragonal embryonic cell tumor, eye cancer, bone malignant fibrous histiocytoma, biliary sac cancer, gastric cancer, gastrointestinal cartinoid tumor, gastrointestinal mesenchymal tumor ( GIST), embryonic cell tumor, gestational chorionic villus tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic nerve Endocrine tumor, kidney cancer, laryngeal cancer, lip and oral cancer, liver cancer, intraepithelial lobular cancer (LCIS), lung cancer, lymphoma, metastatic squamous epithelial cervical cancer of unknown primary, midline cancer, oral cavity Cancer, multiple endocrine tumor syndrome, multiple myeloma / plasma cell line tumor, mycobacterial sarcoma, myelodystrophy syndrome, myelodystrophy / myeloid proliferative tumor, multiple myeloma, Merkel cell carcinoma, malignant lining Tumors, osteomalignant fibrous histiocytoma and osteosarcoma, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity Oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus cancer and nasal cancer, parathyroid cancer, penis cancer, pharyngeal cancer, pleural lung blastoma , Primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional epithelial cancer, retinoblastoma, horizontal print myoma, salivary adenocarcinoma, skin cancer, gastric cancer, small cell lung cancer, small intestine , Soft sarcoma, T-cell lymphoma, testis cancer, pharyngeal cancer, thoracic adenoma and thoracic adenocarcinoma, thyroid cancer, renal meng / urinary tract transition epithelial cancer, vegetative membrane tumor, pediatric rare cancer, urinary tract cancer, Concerning the treatment of subjects with cancers such as uterine sarcoma, vaginal cancer, genital cancer, or virus-induced cancer. In some embodiments, the method relates to the treatment of non-cancerous hyperproliferative disorders such as benign skin hyperplasia (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hyperplasia (BPH)). ..

In some embodiments, the method of treatment is directed to the treatment of lung cancer, such method of administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising it) to a subject in need thereof. including. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers that can be treated with the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors and undifferentiated cancers.

The present disclosure further provides a method of regulating the activity of a G12C variant of a KRAS, HRAS or NRAS protein by contacting the protein with an effective amount of the disclosed compound. The regulation can be inhibition or activation of protein activity. In some embodiments, the disclosure provides a method of inhibiting protein activity by contacting a G12C variant of the KRAS, HRAS or NRAS protein with an effective amount of the disclosed compound solution. In some embodiments, the disclosure provides a method of inhibiting the activity of a G12C mutant KRAS, HRAS or NRAS protein by contacting cells, tissues, or organs expressing the protein of interest. In some embodiments, the disclosure inhibits protein activity in a subject, including but not limited to rodents and mammals (eg, humans), by administering an effective amount of the disclosed compound. Provide a way to do it. In some embodiments, the control rate exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the inhibition rate exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the disclosure comprises an amount of the disclosed compound sufficient to inhibit KRAS, HRAS or NRAS G12C activity in a cell, said cell and KRAS, HRAS or NRAS G12C activity in said cell. Provided is a method of inhibiting by contact. In some embodiments, the present disclosure comprises an amount of the disclosed compound sufficient to inhibit KRAS, HRAS or NRAS G12C activity in a tissue, said tissue and KRAS, HRAS or NRAS G12C activity in said tissue. Provided is a method of inhibiting by contact. In some embodiments, the present disclosure comprises an organism with sufficient amounts of disclosed compound to inhibit the activity of KRAS, HRAS or NRAS G12C in the organism and the activity of KRAS, HRAS or NRAS G12C in the organism. Provided is a method of inhibiting by contact. In some embodiments, the present disclosure comprises an amount of disclosed compound sufficient to inhibit KRAS, HRAS or NRAS G12C activity in an animal, said animal and KRAS, HRAS or NRAS G12C activity in said animal. Provided is a method of inhibiting by contact. In some embodiments, the present disclosure comprises an amount of the disclosed compound sufficient to inhibit KRAS, HRAS or NRAS G12C activity in a mammal, said mammal and KRAS, HRAS or NRAS G12C activity in said mammal. Provided is a method of inhibiting by contact. In some embodiments, the present disclosure comprises an amount of the disclosed compound sufficient to inhibit KRAS, HRAS or NRAS G12C activity in humans, said human and KRAS, HRAS or NRAS G12C activity in said human. Provided is a method of inhibiting by contact. The present disclosure provides a method of treating a disease in a subject requiring treatment of the disease induced by KRAS, HRAS or NRAS G12C activity.

Combination therapy:
The present disclosure also provides a method of combination therapy, in which case other known pathway regulation agents, or other components of the same pathway, or overlapping sets of target enzymes, the compounds of the present disclosure or pharmaceuticals thereof. Use in combination with a commercially acceptable salt. In one aspect, such treatments include combining one or more disclosed compounds with chemotherapeutic agents, therapeutic antibodies, and radiation therapy to obtain synergistic or additive therapeutic effects. , Not limited to this.

Currently, many chemotherapeutic agents are known in the art and can be used in combination with disclosed compounds. In some embodiments, the chemotherapeutic agent is a mitotic agent, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response regulator. It is selected from the group consisting of agents, antihormones, antimetabolites, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gefitinib® (imatinib mesylate), Kyprolis® (carfilzomib), Bortezomib® (registered trademark). Bortezomib), Casodex (vicartamide), Iressa® (gefitinib), and adriamycin, as well as hosts for chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN ™); alkylsulfonic acids such as busulfan, improsulfan and piposulfan; benzodopa, carbocon, methotrexate, and uredopa. Aziridines such as; Altretamine, Triethylenemelamine, Triethylenephosphoramide, Triethylenethiophosphamide and Ethyleneimine and Metilamelamine including Trimethyrolomelamine; Chlorambusyl, Chlornafazine, Corophosphamide, Estramstin, Ifosphamide, Mechloretamine, Mechlore Nitrogen mustards such as tamine oxide hydrochloride, melfaran, nobuenbikin, phenesterin, prednimustin, trophosphamide, uracil mustard; nitrosurea such as carmustin, chlorozotocin, hotemustin, romustin, nimustin, lanimustin; acracinomycin, actinomycin , Azaseline, bleomycin, cactinomycin, calikeamycin, carabicin, carminomycin, cardinophylline, Casodex ™, chromomycin, dactinomycin, daunorubicin, detorbisin, 6-diazo-5-oxo-L-norleucine, Doxorubicin, epirubicin, esorbicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olibomycin, pepromycin, potophilomycin, puromycin, keramicin, rodorubicin, streptnigrin, streptozocin, tubersidin, ubenimex, dinostatin, etc. Antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludalabine, 6-mercaptopurine, thiamipulin, thioguanine Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, citarabin, dideoxyuridine, doxiflulysin, enocitabine, floxiuridine, androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testlactone; Anti-adrenal agents such as glutetimid, mitotan, trilostane; floric acid Folic acid supplements such as; acegraton; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestlabsyl; bisantren; edatraxate; defofamine; demecortin; diazicon; erhomitin; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; Lentinan; lonidamine; mitogazone; mitoxantrone; mopidamole; nitraclin; pentostatin; phenamet; pirarubicin; podophylphosphate; 2-ethylhydrazide; procarbazine; PSK; razoxane; cytarabine; spirogermanium; tenuazonic acid; triadicon; 2,2', 2''-Trichlorotriethylamine; Urethane; Bindesin; Dacarbazine; Mannomustin; Mitobronitol; Mitoxantrone; Pipobroman; Gasitocin; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxanes, such as paclitaxel and docetaxel; retinoic acid Esperamycin; capecitabine; as well as any of the above pharmaceutically acceptable salts, acids or derivatives.

Suitable chemotherapeutic cell regulators include anti-hormonal agents that act to regulate or inhibit hormonal action in tumors, such as tamoxifen, (Nolvadex ™), laroxyfen, aromatase inhibitor 4 (5) -imidazole. Anti-etoposide agents including 4-hydroxytamoxifen, trioxyfen, cheoxyphene, LY117018, onapristone, and tremiphen (fairstone), as well as anti-androgen agents such as flutamide, niltamide, bicartamide, leuprolide, and gocerelin; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastin; platinum; etoposide (VP-16); iphosphamide; mitomycin C; mitoxantrone; bincristin; binorelbin; navelvin; novantron; Also included are daunomycin; aminopterin; Xeloda; ibandronate; camptotesin-11 (CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithin (DMFO).

If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with commonly formulated anticancer agents, such as Herceptin®, Avastin®, Erbitux®. , Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Avagobomab, Acrydin Carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alfaladin, arbosideib, 3-aminopyridine-2-carboxyaldehyde thiosemicarbazone, amonafide, anthracendion, anti-CD22 immunotoxin, antineoplastic drug, antitumor herb, apadicon, atiprimodo, azathiopurine, verotecan, bendamstin, BIBW2992, Billicodal, brostalicin, briostatin, butionine sulfoxymin, CBV (chemotherapy), caliculin, cell cycle non-specific antineoplastic drug, dichloroacetic acid, discodelmolide, elsamitorcin, enocitabine, epotiron, eribulin, elolimus, exatecan, Exislind, Ferguinol, Holodesin, Phosfestol, ICE Chemotherapy Regimen, IT-101, Imexon, Imikimod, Indolocarbazole, Ilofluben, Lanikidal, Larotaxel, Lenalidemid, Lucanton, Lultotecan, Mahosfamide, Mitozolomid, Nahoximab , PAC-1, Popo, Pixantron, Proteasome Inhibitor, Rebeccamycin, Regiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Standford V, Swinesonin, Talaporfin, Tarikidal, Tegafur-Urasyl, Temodar, Tesetaxel There are tryplatin nitrate, tris (2-chloroethyl) amine, troxitabin, uramstin, bazimesan, binflunin, ZD6126 or zoskidal and the like.

The disclosure further relates to methods of using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy for the treatment of inhibition of abnormal cell growth or hyperproliferative disorders in mammals. Techniques for performing radiation therapy are known in the art, and these techniques can be used in the combination therapies described herein. Administration of the disclosed compound in this combination therapy can be determined as described herein.

Radiation therapy can be performed by one of several methods, or a combination of several methods, including, but not limited to, extracorporeal radiation therapy, internal radiation therapy, intra-tissue irradiation, and localization. These include surgical irradiation, systemic radiation therapy, radiation therapy and permanent or temporary insertion brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy that is delivered by inserting a spatially confined radioactive material into or near a tumor site or other proliferative tissue disease site in the body. Point to. Such terms include, but are not limited to, radioactive isotopes such as At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, Exposure to P-32, and the radioactive isotope of Lu) shall be included. Suitable sources for use as cell regulators of the present disclosure include both solids and liquids. As a non-limiting example, the source is a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or photons, beta particles. , Gamma rays, or other radionuclides that emit other therapeutic rays. The radionuclide can be a fluid made from any solution of the radionuclide (s), eg, a solution of I-125 or I-131, or a solid radionuclide such as Au-198, Y-90. It may be a radioactive fluid prepared by using a slurry of a suitable fluid containing the small particles of. In addition, radionuclides (s) are feasible for gels or radiomicrospheres.

The compounds or pharmaceutical compositions of the present disclosure use a combination of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolytic inhibitors, or autophagy inhibitors. be able to.

Anti-angiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors are described in the disclosed compounds and herein. Can be used in combination with the pharmaceutical composition of. Anti-angiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloprotease inhibitors are WO96 / 33172, WO96 / 27583, European Patent Publication No. EP08184442, European Patent Publication No. EP100457, WO98 / 076997, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98. / 33768, WO98 / 30566, European Patent Publication No. 606046, European Patent Publication No. 931788, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO1999007675, European Patent Publication No. EP1786785, European Patent Publication No. EP 1181017, US Publication US 2009001205, US Publication US 5863949, US Publication US 5861510, and European Patent Publication No. EP0780386, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors have little or no MMP-1 inhibitory activity. Other matrix metalloproteinases (ie, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP More preferably, it selectively inhibits MMP-2 and / or AMP-9 with respect to -13). Some specific examples of MMP inhibitors useful in the present disclosure include AG-3340, RO32-3555, and RS13-0830.

The compounds of the present application may be used in combination with other antitumor agents, eg, acemannan, acralubicin, aldesroykin, alemtuzumab, alitretinoin, altretamine, amihostin, aminolevulinic acid, amurubicin, amsacrine, anagrelide, anastrosol, ANCER, Ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexaloten, bicartamide, broxuridine, capecitabin, cellmoloikin, cetrorelix, cladribine, crotrimazole, citalabine ocphosphate, DA3030 (Dong-A), Dakrizumab, Deniroykin Difcitox, Deslorerin, Dexrazoxane, Dirazep, Docetaxel, Docosanol, Doxelcalciferol, Doxyflulysin, Doxorubicin, Bromocryptin, Carmustin, Citarabin, Fluorouracil, Carmustin, Citarabin, Fluorouracil, HIT Diclofenac, Interferon Alpha, Interferon , Eflornitin, Emitefuru, Epirubicin, Epoetin Beta, Etoposide Phosphate, Exemestane, Exislind, Fadrosol, Philgrastim, Finasteride, Fludalabine Phosphate, Holmethan, Hotemstin, Gallium Nitrate, Gemcitabine, Gemtuzumabzogamycin Oteracil / Tegafur combination drug, glycopine, goseleline, heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imikimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon Alpha-2b, Interferon Alpha-N1, Interferon Alpha- _n3 , Interferon Alphacon-1, Interferon Alpha, Natural, Interferon Beta, Interferon Beta-1a, Interferon Beta-1b, Interferon Gamma, Natural Interferon Gamma-1a, Interferon Gamma- 1b, interferon-1 beta, yobenguan, irinotecan, ilsogradin, lanleotide, LC9018 (Yakult), leflunomide, lenograstim, lentinansulfate, retrosol, leukocyte alphain Turferon, Leuprolerin, Revamisol + Fluorouracil, Riarozole, Robaplatin, Ronidamine, Robastatin, Masoprocol, Meralsoprol, Metoclopramid, Mifepriston, Miltehosin, Millimostim, Mismatched double-stranded RNA, Mitoguazone, Mitoxantrone, Mitoxantrone Nafaleline, naloxone + pentazocin, naltograstim, nedaplatin, niltamide, noscapine, novel erythropoiesis stimulating protein, NSC631570 octreotide, oprelbekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alpha-2b, pentosan Sodium, pentostatin, pisivanil, pirarubicin, rabbit anti-chest cell polyclonal antibody, polyethylene glycol interferon alpha-2a, porphimer sodium, laroxyphene, lartitrexed, rasbriembodyment, renium Re186 etidronate, RII retinamide, rituximab, romlucide, samarium (153Sm) Lexidronum, Salgramostim, Cetuximab, Sobzoxane, Sonermin, Strontium Chloride 89, Slamine, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Salidomide, Simulfacin, Tyrotropin alpha Element 131, trastuzumab, treosulfan, tretinoin, trilostane, trimethexate, tryptrelin, tumor necrotizing factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valurubicin, verteporfin, vinorelbine, VIRULIZIN, Dinostatin stimalamer, or zoledronic acid; avalerix; AE941 (Aeterna), ambamustin, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabin, dexaminoglutetimid, diazicon, EL532 ( Elan), EM800 (Endorecherche), Eniluracil, Ethanidazole, Fenretinide, Philgrastim SD01 (Amen), Flubestland, Galocitabin, Gastrin 17 Immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulator, histamine dihydrochloride, ibritsumomabutiuxetane, iromasat, IM862 (Cytran), interleukin-2, iproxifene, LDI200 (Milkhaus), religistim, Linzzumab, CA125MAb (Biomira), Cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Protein), Idiotype CEAMab (CRC Proteiny), Idiotype CEA Techniclone), polymorphic epithelial mucin-itrium 90MAb (antibody), marimasat, melanomaly, mitsumomab, motexafingadrinium, MX6 (Galderma), neralabin, noratrexed, P30 protein, pegbisomant, pemetrexed. RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopotien, ethylethiopurpurin tin, tyrapazamin , Cancer vaccine (Biomira), melanoma vaccine (New York Antibody), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), melanoma cell virus lysate vaccine (Royal ) Or can be used in combination with Balspodal.

The compounds of the invention may also be used with VEGFR inhibitors. Other compounds described in the following patents and patent applications can be used in combination therapies: US6,258,812, US2003 / 0105091, WO01 / 37820, US6,235,764, WO01 / 32651, US6,630, 500, US6,515,004, US6,713,485, US5,521,184, US5,770,599, US5,747,498, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 4509, WO00 / 59509, WO99 / 61422, US5,990,141, WO00 / 12089, and WO00 / 02871.

In some embodiments, the combination comprises at least one anti-angiogenic agent in combination with the compositions of the invention. Drugs include, but are not limited to, chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and complexes thereof prepared by in vitro synthesis. The agent can be an agonist, antagonist, allosteric modulator, toxin, or more generally, inhibit or stimulate its target (eg, activation or inhibition of a receptor or enzyme), thereby promoting cell death. Or it may act to stop cell proliferation.

Exemplary anti-angiogenic agents include Erbitux ™ (IMC-C225), KDR (kinase domain receptor) inhibitors (eg, antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-antigens. VEGF agents (eg, antibodies or antigen binding regions that specifically bind to VEGF or soluble VEGF receptors or their ligand binding regions), such as AVASTIN ™ or VEGF-TRAP ™, and anti-VEGF receptors. Drugs (eg, antibodies or antigen-binding regions that specifically bind to it), EGFR inhibitors (eg, antibodies or antigen-binding regions that specifically bind to it), such as Vectibix (panitumumab), IRESSA ™ (gefitinib) ), TARCEVA ™ (errotinib), anti-Ang1 and anti-Ang2 agents (eg, antibodies or antigen-binding regions that specifically bind to them or their receptors, such as Tie2 / Tek), etc. Also included are anti-Tie2 kinase inhibitors (eg, antibodies or antigen binding regions that specifically bind to it). The pharmaceutical compositions of the present invention include one or more agents (eg, antibodies, antigen binding regions, or soluble receptors) that specifically bind to growth factors and inhibit their activity, such as hepatocyte growth factor (eg, hepatocyte growth factor). Antibodies or antigen-binding regions that specifically bind to the receptor "c-met" such as HGF, antagonists of dispersion factor (also known as Scatter Factor), etc. may also be included.

Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonist (Ceretti et al., US Publication No. 2003/0162712; US Pat. No. 6,413,932), anti-TWEAK agent ( For example, a specifically binding antibody or antigen binding region, or a soluble TWEAK receptor antagonist; see Wiley, US Pat. No. 6,727,225), ADAM disintegral, which antagonizes the binding of integrin to its ligand. Domain (Fanslow et al., US Publication No. 2002/0042368), specifically binding anti-eph receptor and / or anti-effrin antibody or antigen binding region (US Pat. No. 5,981,245; 5,728). , 813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and their patent family members), and anti-PDGF-BB antagonists ( For example, an antibody or antigen-binding region that specifically binds) and an antibody or antigen-binding region that specifically binds to a PDGF-BB ligand, and a PDGFR kinase inhibitor (eg, an antibody or antigen-binding region that specifically binds to it). Is included.

Additional anti-angiogenic / anti-tumor agents include SD-7784 (Pfizer, USA); Sirengitide. (Merck KGaA, Germany, EPO770622); pegaptanib octasodium, (Giled Sciences, USA); alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US5712291); Iromastat, (ArrivaUS), Emaxanib, (Pfizer, USA, US5792783); Bataranib, (Novartis, Switzerland); 2-methoxyestradiol, (EntryMed, USA); TLC ELL-12, (Elan, Ireland); Anecoltab acetate, (Alcon, Acon). Alpha-D148 Mab, (Amen, USA); CEP-7055, (Cephalon, USA); Anti-Vn Mab, (Crucell, Novartis) DAC: Anti-angiogenic drug, (ConjuChem, Canada); Angiogenesis, (InkineAcy) KM-2550, (Kyowa Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, EP970070); ARGENT TECHNOLOGY, (Ariad, USA); YIGSR-Stealth, USA); Fibrinogen-E Fragment, (BioActa, UK); Angiogenesis Inhibitor, (Trigen, UK); TBC-1635, (Encive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntryMed, USA); Angiogenesis Inhibitor, (Tripep, Sweden); Maspin, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203- 00, (IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan); TAN-1120, (Takeda, Japan); FR-111142, (Fujisawa, Japan, JP02233610); Fourth Factor, (RepliGen, USA, EP407122); Angiogenesis Inhibitor Proliferation Factor Anta Gonist, (Borean, Denmark); bevacizumab (pINN), (Genentech, USA); angiogenesis inhibitor, (SUGEN, USA); XL784, (Exelixis, USA); XL647, (Exelixis, USA); MAb, alpha 5 Bevacizumab, 2nd Generation, (Applied Molecular Evolution, USA and MedImmune, USA); Gene Therapy, Retinopathy, (Oxford BioMedica, UK); Enzastauline Hydrochloride (USA), (Lilly, USA); CEP7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC1, (Genoa Institute of Cancer Research, Italy); Angiogenesis Inhibitors, (Alchemia, Australia); Derived from VEGF antagonist, (Regen), (Regen) Anti-angiogenic agents, (XOMA, USA); PI88, (Progen, Australia); Sirengitide (pINN), (Merck KGaA, German; Munich Technical Universal University, Germany, Cetuximab, Cetuximab, Cetuximab, Cetuximab (Aventis, France); AVE8062, (Ajinomoto, Japan); AS1404, (Cancer Research Laboratory, New Zealand); SG292, (Telios, USA); Endostatin, (BostonHistonTsN); ); Angiogenesis, (Boston Children Hospital, USA); 2-methoxyestradiol, (Boston Children Hospital, USA); ZD6474, (AstraZeneca, UK); ZD6126, (AngiogenePace), (AngiogenePharmaces) AZD9935, (AstraZeneca, UK); AZD2171, (AstraZeneca, UK) ); Bataranib (pINN), (Novartis, Pfizerland and Schering AG, Germany); Tissue factor pathway inhibitor, (EntryMed, USA); Pegaptanib (Pinn), (Gilead Sciences, USA); Xanthrizol, (Yonse) South Korea); Gene Vaccine, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX103, (University of California; ); Metastatin, (EntryMed, USA); Troponin I, (Harvard Vaccine, USA); SU6668, (SUGEN, USA); OXI4503, (OXiGENE, USA); o-guanidine, (Dimensional Pharmaceutical, USA); (British Columbia University, Canda); CDP791, (Celltech Group, UK); Achiprimod (pINN), (GlaxoSmithKline, UK); E7820, (Eisai, Japan); Canda); Vaccine, Angiogenesis, (EntreMed, USA); Urokinase Plusminogen Activation Inhibitor, (Dendren, USA); Oglufanide (pINN), (Melmotte, USA); HIF-1 Alpha Inhibitor, (Xenova, UK) CEP5214, (Cephalon, USA); BAY RES2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR31372, (Korea Research Institut, PowerSome, USA); (GlaxoSmithKline, UK); EHT0101, (ExonHit, France); CP868596, (Pfizer) , USA); CP564959, (OSI, USA); CP547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN633, (Kirin Brewery, Japan); Drug Delivery System, Intraocular, 2-methoxyestradiol, (USA); EntreMed, USA); Angenex, (Maastricht University, Netherlands, and Minnesota University, USA); ABT510, (Abbott, USA); AAL993, (Novart, USA); , (National Institute on Aging, USA); SU11248, (Pfizer, USA and SUGEN USA); ABT518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (Bonst), , USA); MAb, KDR, (ImClone Systems, USA); MAb, Alpha 5 Beta 1, (Protein Design, USA); KDR kinase inhibitor, (Celltech Group, UK, and Johnson & Johnson, USA); GFB116, (South). Florida University, USA and Yale University, USA); CS706, (Sankyo, Japan); Combretastatin A4 Prodrug, (Arizona State University, USA); Chondroitinase AC, (IBA) , Germany); AGM1470, (Harvard University, USA, Takeda, Japan, and TAP, USA); AG13925, (Agouron, USA); Tetrathiomolibdate, (University of Michigan, USA); USA) CV247, (Ivy Medical, UK); CKD732, (Chong Kun Dang) , South Korea; MAb, Vascular Endothelial Growth Factor, (Xenova, UK); Ilsogradin (INN), (Nippon Shinyaku, Japan), RG13577, (Aventis, France); WX360, (Wilex, Germany); ), (Geneera, USA), RPI4610, (Sirna, USA); Cancer Treatment, (Marinova, Australia); Heparanase Inhibitor, (InSight, Israel); KL3106, (Kolon, South Korea); Honokiol, (Emor). , USA); ZK CDK, (Schering AG, Germany); ZK Angio, (Schering AG, Germany); ZK229561, (Novartis, Switzerland, and Schering AG, Germany); XMP300, (XOMA, USA); , Japan); VEGF receptor regulator, (Pharmacopea, USA); VE-cadherin-2 antagonist, (ImClone Systems, USA); Basostatin, (National Institutes of Health, USA); Vaccine, Flk-1, (ImClone). , USA); TZ93, (Tsumura, Japan); Tamstatin, (Beth Israel Hospital, USA); Cleaved soluble FLT1 (Vascular Endothelial Growth Factor Receptor 1), (Merck & Co, USA); Tie-2 Ligand, (Regeneron) , USA); as well as thrombospondin 1 inhibitor, (Allegheny Health, Education and Research Foundation, USA).

Autophagy inhibitors include chloroquine, 3-methyladenosine, hydroxychloroquine (Plaquenil ™), bafilomycin A1, 5-amino-4-imidazolocarboxamideriboside (AIPAR), okadaic acid, type 2A or type 1. Includes, but is not limited to, autophagy-suppressing algae toxins that inhibit protein phosphatase, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurineriboside, and vinblastin. Absent. In addition, antisense or siRNA that inhibits protein expression may be used, including but not limited to ATG5 (involved in autophagy).

Additional pharmaceutically active compounds / agents that can be used to treat cancer and can be used in combination with one or more of the compounds of the invention include epoetin alfa; dalbepoetin alfa; panitumumab; pegfilgrastim; parifermin; filgrastim. Denosumab; Ancestim; AMG102; AMG386; AMG479; AMG655; AMG745; AMG951 and AMG706, or pharmaceutically acceptable salts thereof.

In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents include naturally occurring substances such as vinca alkaloids (eg vinblastin, vincristin, and binorerbin), paclitaxel, epidipodophylrotoxins (eg etoposide and teniposide), antibiotics (eg duck). Enzymes (eg, L-aspartin systemically metabolize and self L-asparaginase, which deprives cells that are incapable of synthesizing asparagine), antiplatelet drugs, antiproliferative / anti-thread division alkylating agents, such as nitrogen mustards (eg, methotrexate, analogs to cyclophosphamide, CDK inhibitors (eg, sericicrib, UCN-01, P1446A-05, PD-0332991, dynacyclib, P27-00, AT) such as melphalan and chlorambusyl), ethyleneimine and methylmelamine (eg, hexamethylmelamine and thiotepa). -7519, RGB286638, and SCH72765), alkylsulfonic acid (eg, busulfan), nitrosourea (eg, carmustin (BCNU) and analogs, and streptozocin), trazen-dacarbazinin (DTIC), antiproliferative / anti-thread splitting Antimetabolites such as folic acid analogs (eg methotrexate), pyrimidine analogs (eg fluorouracil, floxiuridine, and citarabin), purine analogs and related inhibitors (eg mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxy) Adenosine), aromatase inhibitors (eg, anastrosol, exemethan, and retrosol), and platinum coordination complexes (eg, cisplatin and carboplatin), such as procarbazine, hydroxyurea, mitotan, aminoglutetimide, histone deacetylation. (HDAC) inhibitors (eg, tricostatin, sodium butyrate, apicidan, suberoylanilide hydrochiamic acid, bolinostat, LBH589, lomidepsin, ACY-1215, and panobinostat), mTor inhibitors (eg, temcilolims, eberolimus, lidahololims, and Shirolimus), KSP (Eg5) inhibitor (eg, Array520), DNA binder (eg, Zari) Psis), PI3K delta inhibitors (eg GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (eg CAL-130), multiple kinase inhibitors (eg TG02 and sorafenib), hormones (eg estrogen) ) And hormone agonists, such as luteinizing hormone-releasing hormone (LHRH) agonists (eg, gocerelin, leuprolide and tryptreline), BAFF-neutralizing antibodies (eg, LY21237399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (eg. For example, CNTO328), telomerase inhibitors (eg, GRN163L), aurora kinase inhibitors (eg, MLN8237), cell surface monoclonal antibodies (eg, anti-CD38 (HUMAX-CD38), anti-CS1 (eg, erotuzumab), HSP90 inhibitors. (Eg, 17AAG and KOS953), P13K / Akt inhibitor (eg, perihocin), Akt inhibitor (eg, GSK-21471795), PKC inhibitor (eg, Enzastauline), FTI (eg, Zarnestra ™) , Anti-CD138 (eg, BT062), Torc1 / 2 specific kinase inhibitor (eg, INK128), kinase inhibitor (eg, GS-1101), ER / UPR targeting agent (eg, MKC-3946), cFMS inhibitor (Eg, ARRY-382), JAK1 / 2 inhibitors (eg, CYT387), PARP inhibitors (eg, olaparib and veriparib (ABT-888)), BCL-2 antagonists may be included. Other chemotherapeutic agents may include chlormethine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelvin, sorafenib, or any analog or derived variant of the chemotherapeutic agent described above.

The compounds of the present invention may be used in combination with radiation therapy, hormone therapy, surgery and immunotherapy, therapies thereof are well known to those of skill in the art.

In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnenolone, alcromethazone, algeston, amcinonide, bechrometasone, betamethazone, budesonide, chloroprednisolone, clobetazol, crocortron, cloprednisolone, corticosterone, cortisone, cortibazole, defrazacolt, desonide, desoxymethazone. , Dexamethasone, diflorazone, diflucortron, diphprednisolone, enoxolone, fluazacolt, fluchloronide, flumethasone, flunisolide, fluocinolone acetnide, fluocinonede, fluocortinbutyl, fluorocortron, fluorometholone, fluperolone acetate, fluprednisolone Acetate, fluprednisolone, fullland lenolide, fluticazone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, roteprednisolone etabonate, magipredone, medrisone, meprednisolone, methylprednisolone, mometasone Carous acid ester, parameterzone, prednisolone, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisolone, prednisolone, prednisolone, rimexolone, thixocortor, triamcinolone, triamcinolone, acetonide, triamcinolone, triamcinolone Examples include, but are not limited to, nid and its salts and / or derivatives. In certain embodiments, the compounds of the invention can be used in combination with additional pharmaceutically active agents to treat nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

The compounds or pharmaceutical compositions of the present disclosure also include any amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and anti-PD-1,. It can also be used in combination with immunotherapy including anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), saltumumab, nimotuzumab, and pinezumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently lapatinib (Tykerb). For example, Yan L, et. al. , Pharmacogenomics and Pharmacogenomics In Oncology Therapeutic Antibodies Development, BioTechniques 2005; 39 (4): 565-8, and Paez JG, et. al. , EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304 (5676): 1497-500.

Non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described in the following publications, as well as all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European patent application EP520722 (publication date December 30, 1992); European patent application EP566226 (publication date October 20, 1993); PCT International Publication WO96 / 33980 (publication date October 31, 1996); US patent Nos. 5,747,498 (Issued May 5, 1998); PCT International Publication WO 96/30347 (Published October 3, 1996); European Patent Application EP787772 (Published August 6, 1997) PCT International Publication WO97 / 30043 (Publication date August 21, 1997); PCT International Publication WO97 / 30041 (Publication date August 21, 1997); PCT International Publication WO97 / 38994 (Publication date October 1997) March 23); PCT International Publication WO97 / 49688 (Published December 31, 1997); European Patent Application EP837063 (Published April 22, 1998); PCT International Publication WO98 / 02434 (Published 1998) January 22); PCT International Publication WO97 / 38983 (publication date October 23, 1997); PCT International Publication WO95 / 19774 (publication date July 27, 1995); PCT International Publication WO95 / 19970 (publication date July 27, 1995) Publication date July 27, 1995); PCT international publication WO97 / 13771 (publication date April 17, 1997); PCT international publication WO98 / 02437 (publication date January 22, 1998); PCT international publication WO98 / 02438 (Publication date: January 22, 1998); PCT International Publication WO97 / 32881 (Publication date: September 12, 1997); German application DE19629652 (Publication date: January 29, 1998); PCT International Publication: WO98 / 33798 (Publication date: August 6, 1998); PCT International Publication WO97 / 32880 (Publication date: September 12, 1997); PCT International Publication: WO97 / 32880 (Publication date: September 12, 1997); European patent application EP682027 (publication date: November 15, 1995); PCT international publication WO97 / 02266 (publication date: January 23, 1997); PCT international publication WO97 / 27199 (publication date: July 31, 1997) PCT International Publication WO98 / 07726 (Published February 26, 1998); PC T International Publication WO97 / 34895 (Published September 25, 1997); PCT International Publication WO96 / 31510'(Published October 10, 1996); PCT International Publication WO98 / 14449 (Published April 1998) May 9); PCT International Publication WO98 / 14450 (Publication date April 9, 1998); PCT International Publication WO98 / 14451 (Publication date April 9, 1998); PCT International Publication WO95 / 09847 (Publication) Date April 13, 1995); PCT International Publication WO97 / 19065 (Publication date May 29, 1997); PCT International Publication WO98 / 17662 (Publication date April 30, 1998); US Patent No. 5 789,427 (issue date: August 4, 1998); US Pat. No. 5,650,415 (issue date: July 22, 1997); US Pat. No. 5,656,643 (issue date: August 1997) 12th May); PCT International Publication WO99 / 35146 (Publication date July 15, 1999); PCT International Publication WO99 / 35132 (Publication date July 15, 1999); PCT International Publication WO99 / 07701 (Publication) (February 18, 1999); and PCT International Publication WO92 / 20642 (Published November 26, 1992). Further non-limiting examples of low molecular weight EGFR inhibitors include Traxler, P. et al. , 1998, Exp. Opin. The. Patents 8 (12): Includes any of the EGFR inhibitors described in 1599-1625.

Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment whose natural ligand can partially or completely block EGFR activation. Non-limiting examples of antibody-based EGFR inhibitors include Modjtahedi, H. et al. , Et al. , 1993, Br. J. Cancer 67: 247-253; Teramoto, T. et al. , Et al. , 1996, Cancer 77: 639-645; Goldstein et al. , 1995, Clin. Cancer Res. 1: 1311-1318; Huang, S. et al. M. , Et al. , 1999, Cancer Res. 15:59 (8): 1935-40; and Yang, X. et al. , Et al. , 1999, Cancer Res. 59: 1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having binding specificity thereof.

MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318888, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

PI3K inhibitors include waltmannin, a 17-hydroxywaltmannin analog described in WO 06/044453, 4- [2- (1H-indazole-4-yl) -6-[[4- (methylsulfonyl)). Piperazin-1-yl] methyl] thieno [3,2-d] pyrimidin-4-yl] morpholine (also known as GDC0941, described in PCT Publications WO09 / 036,082 and WO09 / 055,730), 2-Methyl-2- [4- [3-Methyl-2-oxo-8- (quinoline-3-yl) -2,3-dihydroimidazo [4,5-c] quinoline-1-yl] phenyl] pro Pionitrile (also known as BEZ235 or NVP-BEZ235, described in PCT Publication No. WO 06/122806), (S) -1-(4-((2- (2-aminopyrimidine-5-yl))- 7-Methyl-4-morpholinothioeno [3,2-d] pyrimidin-6-yl) methyl) piperazin-1-yl) -2-hydroxypropan-1-one (described in PCT publication number WO2008 / 070740), LY294002 (2- (4-morpholinyl) -8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI103 hydrochloride (3- [4- (4-morpholinyl pyrido- [3) ′, 2 ′: 4,5] Flo [3,2-d] pyrimidin-2-yl] phenol hydrochloride, available from Axon Methyl), PIK75 (N'-[(1E)-(6-bromoimidazole] 1,2-a] pyridine-3-yl) methylene] -N, 2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride, available from Axon Medchem), PIK90 (N- (7,8-dimethoxy-2) , 3-Dihydro-imidazole [1,2-c] quinazoline-5-yl) -nicotinamide, available from Axon Methyl), GDC-0941 bismesylate (2- (1H-indazole-4-yl) -6- ( 4-Methanesulfonyl-piperazin-1-ylmethyl) -4-morpholine-4-yl-thieno [3,2-d] pyrimidin bismesylate, available from Axon Medchem), AS-25224 (5- [1-[ 5- (4-fluoro-2-hydroxy-phenyl) -furan-2-yl] -methyl- (Z) -iriden] -thiazolidine-2,4-dione, Axon Medchem (Available), and TGX-221 (7-methyl-2- (4-morpholinyl) -9- [1- (phenylamino) ethyl] -4H-pyrido- [1,2-a] pyrimidin-4-one , Available from Axon Medchem), XL-765, and XL-147, but are not limited thereto. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, paromid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100. , CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

Examples of AKT inhibitors include Akt-1-1 (inhibiting Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1, 2 (Ak1). And Ak2) (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (eg, Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo [4,5-c] pyridinyl compound (eg, WO05011700); indol-3-carbinol and its derivatives (eg, US Pat. No. 6,656,963; Sarkar and Li). (2004) J Nutr. 134 (12 Suppl), 3493S-3298S); perihosin (eg, interfering with Akt membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res. 10 (15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (eg, Gills and Dennis (2004) Expert.Opin.Investig.Drugs13,787-97); and tricilibine (TCN or API-2 or NCI identifier: NSC154020; Yang et al. 2004) Cancer Res. 64, 4394-9), but is not limited to this.

TOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors, such as PI-103, PP242, PP30 and Torin1. However, it is not limited to this. FKBP12 enhancer; other TOR inhibitors contained in rapamycin and its derivatives are disclosed in CCI-779 (temsirolimus), RAD001 (everolimus; WO94009010) and AP23573; rapalogs such as WO98 / 02441 and WO01 / 14387. , For example, rapalogs such as AP23573, AP23464, or AP23841; 40- (2-hydroxyethyl) rapamycin, 40- [3-hydroxy (hydroxymethyl) methylpropanoart] -rapamycin (also called CC1779), 40-epi- (Temsirolimus) -rapamycin (also called ABT578), 32-deoxorapamycin, 16-pentynyloxy-32 (S) -dihydrorapanaicin, and other derivatives disclosed in WO05005434; US Pat. No. 5,258,389; , WO94 / 090101, WO92 / 05179, US Pat. No. 5,118,677, US Pat. No. 5,118,678, US Pat. No. 5,100,883, US Pat. No. 5,151,413, US Pat. Patent Nos. 5,120,842, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and US Patent No. 5,256,790. Disclosed derivatives; phosphorus-containing rapamycin derivatives (eg, WO05016252); 4H-1-benzopyran-4-one derivatives (eg, US Provisional Patent Application No. 60 / 528,340).

Immunotherapy includes, but is not limited to, anti-PD-1, anti-PDL-1, anti-CTLA-4, anti-LAG1, and anti-OX40 agents. An exemplary anti-PD-1 antibody and method of its use are described in Goldberg et al. , Blood 110 (1): 186-192 (2007), Thompson et al. , Clin. Cancer Res. 13 (6): 1757-1761 (2007), and Korman et al. It is described by International Application No. PCT / JP2006 / 309606 (Publication No. WO2006 / 121168A1), each of which is expressly incorporated herein by reference, which includes Yervoy ™ (ipilimumab) or Tremerimumab (anti). CTLA-4), galiximab (anti-B7.1), BMS-936558 (anti-PD-1), MK-3475 (anti-PD-1), AMP224 (anti-B7DC), BMS-936559 (anti-B7-H1), MPDL3280A (Anti-B7-H1), MEDI-570 (Anti-ICOS), AMG557 (Anti-B7H2), MGA271 (Anti-B7H3), IMP321 (Anti-LAG-3), BMS-663513 (Anti-CD137), PF-05082566 (Anti-CD137) , CDX-1127 (anti-CD27), anti-OX40 (Providence Health Services), huMAbOX40L (anti-OX40L), Atacicept (anti-TACI), CP-870893 (anti-CD40), lucatumumab (anti-CD40), dasetsumumab (anti-CD40) -CD3 (anti-CD3), ipilimumab (anti-CTLA-4) is included. Immunotherapy also includes genetically engineered T cells (eg, CAR-T cells) and bispecific antibodies (eg, BiTE).

GITR agonists include GITR fusion proteins and anti-GITR antibodies (eg, divalent anti-GITR antibodies), such as US Pat. No. 6,111,090 box. c, GITR fusion proteins or anti-GITR antibodies described in European Patent No. 090505B1, US Pat. No. 8,586,023, PCT Publication Nos. WO2010 / 003118 and 2011/090754, eg, US Pat. No. 7,025,962. No., European Patent No. 1947183B1, US Patent No. 7,812,135, US Patent No. 8,388,967, US Patent No. 8,591,886, European Patent No. EP18663339, PCT Publication No. WO2011 / 028683 , PCT Publication No. WO2013 / 039954, PCT Publication No. WO2005 / 07190, PCT Publication Number WO2007 / 133822, PCT Publication Number WO2005 / 055808, PCT Publication Number WO99 / 40196, PCT Publication Number WO2001 / 03720, PCT Publication Number WO99 / 20758, Examples thereof include, but are not limited to, those described in PCT Publication No. WO2006 / 083289, PCT Publication No. WO2005 / 115451, US Pat. No. 7,618,632, and PCT Publication No. WO2011 / 051726.

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害薬（カルフィルゾミブまたはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブ）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブ）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

を有する化合物またはその立体異性体、そのアトロプ異性体、その薬学的に許容される塩、その立体異性体の薬学的に許容される塩、もしくはそのアトロプ異性体の薬学的に許容される塩を、それを必要とする患者に対し、治療的有効量の薬学的に活性なさらなる化合物、例えば、シタラビン、プロテアソーム阻害剤（カルフィルゾミブもしくはオプロゾミブなど）、ＢＣｌ−_２阻害剤（ベネトクラクスなど）、ＭＣｌ−_１阻害剤（ＡＭＧ−_１７６など）、モノクローナル抗体（ダラツムマブなど）、及び免疫調節イミド薬（ＩＭｉＤ）（サリドマイド、レナリドミド、ポマリドミド及びアプレミラストなど）と投与する。 In some embodiments, the structure

A compound having a compound or a steric isomer thereof, an atrop isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the steric isomer, or a pharmaceutically acceptable salt of the atrop isomer thereof. For patients in need of it, therapeutically effective amounts of additional pharmaceutically active compounds, such as citalabine, proteasome inhibitors (such as carfilzomib or oprosomib), BCl- ₂ inhibitors (such as lenalidomide), MCl- _1. Administer with inhibitors (such as AMG- ₁₇₆ ), monoclonal antibodies (such as daratumumab), and immunomodulatory imide drugs (IMiD) (such as thalidomide, lenalidomide, pomaridomide and apremilast).

The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the pathology to be treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other agents as described above. When the compounds described herein are used in combination therapy, they are administered simultaneously or separately with a second agent. This combination administration may include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in individual dosage forms, and individual administration. That is, the compound described in the present specification and any of the above drugs can be combined into the same dosage form and co-administered. Alternatively, the disclosed compound and any of the above agents can be co-administered, where both agents are included in separate formulations. In another alternative method, any of the above agents may be administered after administration of the compounds of the present disclosure, or vice versa. In some embodiments of the individual dosing protocol, the disclosed compound and any of the above agents are administered at intervals of minutes, hours, or days.

As an aspect of the present invention, treatment of a disease / pathological condition using a combination of pharmaceutically active compounds that can be administered separately is intended, and the present invention relates to further combining separate pharmaceutical compositions into a kit form. The kit comprises two distinct pharmaceutical compositions, a compound of the invention and a second pharmaceutical compound. The kit includes containers for containing separate compositions, such as split bottles or split foil packets. Further examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for using the separate components. Kit forms include individual components that are preferably administered in different dosage forms (eg, oral and parenteral dosage forms), at different dosing intervals, or in combination by a prescribing healthcare professional. This is especially convenient if you want a gradual increase in.

ステップ１：２−アミノ−４−ブロモ−５−クロロ−３−フルオロ安息香酸（中間体Ａ）。
２−アミノ−４−ブロモ−３−フルオロ安息香酸（３．９１ｇ、１６．７１ｍｍｏｌ、Ａｐｏｌｌｏ Ｓｃｉｅｎｔｉｆｉｃ Ｌｔｄ．、Ｓｔｏｃｋｐｏｒｔ、ＵＫ）とＮ−クロロスクシンイミド（１．３６ｍＬ、１６．７ｍｍｏｌ）との混合Ｎ，Ｎ−ジメチルホルムアミド溶液（３３ｍＬ）を７０℃で２０時間撹拌した。その後、反応混合物を室温まで冷却し、氷水（４０ｍＬ）を加え、得られた混合物を１時間撹拌した。生じた析出物をろ過によって回収し、水で洗浄してから真空乾燥させ、２−アミノ−４−ブロモ−５−クロロ−３−フルオロ安息香酸が得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ７．６９ （１Ｈ、ｄ、Ｊ ＝ ２．０ Ｈｚ）、６．４８−７．２３ （２Ｈ、ｂｒ ｓ）。 ^１９Ｆ ＮＭＲ （３７６ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ −１１９．７０ （１Ｆ、ｓ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ２７０．０ （Ｍ＋Ｈ）^＋。 Method 1
Example 1-1: 1- (4- (6- (2-bromo-5-hydroxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl) propa -2-en-1-on

Step 1: 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (Intermediate A).
Mixing N, 2-amino-4-bromo-3-fluorobenzoic acid (3.91 g, 16.71 mmol, Apollo Scientific Ltd., Metropolitan, UK) with N-chlorosuccinimide (1.36 mL, 16.7 mmol) The N-dimethylformamide solution (33 mL) was stirred at 70 ° C. for 20 hours. The reaction mixture was then cooled to room temperature, ice water (40 mL) was added and the resulting mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and then vacuum dried to give 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (1 H, d, J = 2.0 Hz), 6.48-7.23 (2 H, br s). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ 119.70 (1 F, s). m / z (ESI, + ve) 270.0 (M + H) ⁺ .

Step 2: 2-Amino-4-bromo-5-chloro-3-fluorobenzamide (Intermediate B).
2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (intermediate A, 3.96 g, 14.7 mmol) and TBTU (4.97 g, 15.5 mmol, Advanced ChemTech, Louisville, KY, USA) Ammonium chloride (1.10 g, 20.6 mmol) and diisopropylethylamine (5.13 mL, 29.5 mmol) were sequentially added to an N, N-dimethylformamide solution (30 mL), and the obtained mixture was added to 30 at room temperature. Stir for minutes. Then, the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with water and then vacuum dried to give 2-amino-4-bromo-5-chloro-3-fluorobenzamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (1H, br s), 7.72 (1H, d, J = 2.0 Hz), 7.47 (1H, br s), 6 .86 (2H, s). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-120.79 (1F, s). m / z (ESI, + ve) 268.9 (M + H) ⁺ .

Step 3: 2-Amino-4-bromo-5-chloro-3-fluorobenzothioamide Lawesson's reagent (2.81 g, 6.95 mmol) was added to 2-amino-4-bromo-5-chloro-3-fluorobenzamide (2.81 g, 6.95 mmol). Intermediate B, 3.10 g, 11.59 mmol) was added to a THF solution (77 mL) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc (75 mL) and washed successively with 2M aqueous HCl (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saline (50 mL). Then, the organic extract was dried over Na ₂ SO ₄ , collected by filtration and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-3% MeOH) to give 2-amino-4-bromo-5-chloro-3-fluorobenzothioamide: ¹ H NMR (400 MHz, DMSO-d _6). ) Δ 9.93-1.15 (1H, m), 9.63 (1H, br s), 7.28 (1H, d, J = 1.96 Hz), 6.34 (2H, s). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -119.52 (1 F, s). m / z (ESI, + ve) 284.8 (M + H) ⁺ .

Step 4: 6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-amine hydrogen peroxide (30 wt% in water, 2.93 mL, 28.7 mmol) 2-amino-4-bromo It was added dropwise to an ice-cooled pyridine solution (32 mL) of -5-chloro-3-fluorobenzothioamide (2.71 g, 9.55 mmol), followed by warming the resulting mixture to room temperature and stirring for 24 hours. .. Water (50 mL) was added and the precipitated solid was collected by filtration, washed with water and then vacuum dried to obtain 6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-amine. T: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.12-8.26 (2 H, m), 7.95-8.06 (1 H, m). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-114.32 (1 F, s). m / z (ESI, + ve) 283.0 (M + H) ⁺ .

Step 5: 6-Bromo-3,5-dichloro-7-fluorobenzo [c] isothiazole (Intermediate C)
Ice of 6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-amine (2.47 g, 8.78 mmol), water (12 mL), and concentrated hydrochloric acid (37 wt%, 12 mL, 395 mmol) An aqueous solution (2.0 mL) of sodium nitrite (0.788 g, 11.4 mmol) was slowly added to the cooled mixture. The resulting mixture was stirred at 0 ° C. for 2.5 hours, followed by 0 of a mixture of copper (I) chloride (1.39 g, 14.1 mmol) dissolved in concentrated hydrochloric acid (37 wt%, 12 mL, 395 mmol). Added at ° C. Subsequently, the reaction mixture was heated to room temperature and stirred for 20 hours. The reaction mixture was diluted with water (50 mL), and the precipitated solid was collected by filtration and dried under vacuum. The recovered material was taken up in DCM: MeOH (3: 1) (200 mL) and washed with water (200 mL) and saline (100 mL) in that order. Then, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptan containing 0-20% EtOAc) to give 6-bromo-3,5-dichloro-7-fluorobenzo [c] isothiazole: ¹ H NMR (400 MHz, DMSO). −D ₆ ) δ 7.99 (1H, d, J = 1.57 Hz). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-111.48 (1 F, s). m / z (ESI, + ve) 425.0 (M + H) ⁺ .

Step 6: 4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (intermediate D)
Mixing N, N- of 6-bromo-3,5-dichloro-7-fluorobenzo [c] isothiazole (Intermediate C, 150 mg, 0.497 mmol) and 1-Boc-piperazine (204 mg, 1.09 mmol) The dimethylformamide solution (2.0 mL) was stirred at room temperature for 20 hours. The reaction mixture is then adsorbed on silica gel, purified by chromatography (silica gel, heptane containing EtOAc 0-20%) and 4- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl). ) Piperazine-1-carboxylate tert-butyl was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ 7.60 (1H, d, J = 1.56 Hz) 3.68-3.79 (4H, m) 3.40-3.51 (4H) , M), 1.26 (9H, s). m / z (ESI, + ve) 451.8 (M + H) ⁺ .

Step 7: 4- (6- (2-Bromo-5-methoxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazin-1-carboxylate tert-butyl 4- (6) -Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazin-1-carboxylate tert-butyl (intermediate D, 111 mg, 0.247 mmol), 2-bromo-5-methoxybenzene 1,4 in which a mixture of boronic acid (0.114 mL, 0.494 mmol), sodium carbonate (0.041 mL, 0.988 mmol), and tetrakis (triphenylphosphine) palladium (14.3 mg, 0.012 mmol) was dissolved. -A mixture of dioxane solution (1.6 mL) and water (0.4 mL) was heated at 90 ° C. for 21 hours. The reaction mixture is then concentrated under reduced pressure, adsorbed on silica gel, purified by column chromatography (silica gel, EtOAc / EtOH (3: 1) 0-20% heptan) and 4- (6- (2-bromo). -5-methoxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl was given: m / z (ESI, + ve) 558.1 ( M + H) ⁺ .

Step 8: 1- (4- (6- (2-bromo-5-hydroxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2- En-1-one hydrogen chloride (4M, 1,4-dioxane solution, 2.0 mL, 8.0 mmol), 4- (6- (2-bromo-5-methoxyphenyl) -5-chloro-7-fluoro Add to a mixture of tert-butyl benzo [c] isothiazole-3-yl) piperazine-1-carboxylate (107 mg, 0.192 mmol) and methanol (2.0 mL) and stir the resulting mixture at room temperature for 1 hour. did. The reaction mixture was then concentrated under reduced pressure to give 6- (2-bromo-5-methoxyphenyl) -5-chloro-7-fluoro-3- (piperazine-1-yl) benzo [c] isothiazole: m / z (ESI, + ve) 458.0 (M + 1) ⁺ .

A dichloromethane solution (2 mL) of N, N-diisopropylethylamine (0.101 mL, 0.578 mmol) was added to this material (88 mg), and the resulting mixture was cooled to 0 ° C. Acryloyl chloride (0.26 M DCM solution, 0.75 mL, 0.19 mmol) was added and the resulting mixture was stirred at 0 ° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure and 1- (4- (6- (2-bromo-5-methoxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl). Propa-2-en-1-one was obtained: m / z (ESI, + ve) 512.0 (M + H) ⁺ .

For compounds without a methyl ether protecting group, the crude material was purified at this stage. For compounds with a methyl ether protecting group, the crude material was used in the next conversion without purification.

The obtained 1- (4- (6- (2-bromo-5-methoxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2- En-1-one was taken up in 1,2-dichloroethane (2.0 mL) and cooled to 0 ° C. A boron tribromide solution (1.0 M hexane solution, 0.97 mL, 0.97 mmol) was added and the resulting mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was then added to saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and extracted with DCM / MeOH (2: 1) (10 mL). The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, DCM containing 0-3% MeOH) and 1- (4- (6- (2-bromo-5-hydroxyphenyl) -5-chloro-7-fluorobenzo [c] isothiazole). −3-Il) Piperazin-1-yl) Propa-2-en-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (br s, 1 H), 8. 04 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.81-6.94 (m, 2H), 6.79 (d, J = 2.9) Hz, 1H), 6.19 (dd, J = 16.7, 2.2 Hz, 1H), 5.77 (dd, J = 10.5, 2.2 Hz, 1H), 3. 87 (br d, J = 19.5 Hz, 4 H), 3.63 (br t, J = 5.1 Hz, 4 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-124.16 (1F, s). m / z (ESI, + ve) 498.0 (M + H) ⁺ .

ステップ１：２−アミノ−６−ブロモ−５−クロロニコチン酸。
Ｎ‐クロロスクシンイミド（２．７８ｇ、２０．８ｍｍｏｌ）を、２−アミノ−６−ブロモニコチン酸（４．５１ｇ、２０．８ｍｍｏｌ、Ａｒｋ Ｐｈａｒｍ Ｉｎｃ．Ａｒｌｉｎｇｔｏｎ Ｈｅｉｇｈｔｓ、ＩＬ、ＵＳＡ）のＤＭＦ溶液（７５ｍＬ）に加え、得られた混合物を７０℃で２．５時間加熱した。その後、加熱を中止し、撹拌を１６時間継続した。続いて反応混合物を氷水に注いだ。氷解後、得られたスラリーをフリットガラス漏斗に通してろ過した。回収した固体を風乾し、２−アミノ−６−ブロモ−５−クロロニコチン酸を得た：^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ８．０５ （ｓ、１Ｈ）、７．６４ （ｂｒ． ｓ、２Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ２５０．９ （Ｍ＋Ｈ）^＋。 Method 2
Examples 21: 1- (4- (5-chloro-6- (3-hydroxy-1-naphthalenyl) [1,2] thiazolo [3,4-b] pyridin-3-yl) -1-piperazinyl ) -2-Propene-1-on

Step 1: 2-Amino-6-bromo-5-chloronicotinic acid.
N-Chlorosuccinimide (2.78 g, 20.8 mmol) in DMF solution (75 mL) of 2-amino-6-bromonicotinic acid (4.51 g, 20.8 mmol, Ark Pharm Inc. Arlington Heights, IL, USA) In addition, the resulting mixture was heated at 70 ° C. for 2.5 hours. Then, heating was stopped and stirring was continued for 16 hours. The reaction mixture was then poured into ice water. After thawing, the resulting slurry was passed through a frit glass funnel and filtered. The recovered solid was air dried to give 2-amino-6-bromo-5-chloronicotinic acid: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H), 7.64 ( br. S, 2H). m / z (ESI, + ve) 250.9 (M + H) ⁺ .

Step 2: tert-butyl 4- (2-amino-6-bromo-5-chloronicotinoyyl) piperazine-1-carboxylate.
TBTU (1.93 g, 6.0 mmol) was added to a DMF solution (14 mL) of 2-amino-6-bromo-5-chloronicotinic acid (1.12 g, 4.5 mmol). After 5 minutes, the reaction was treated sequentially with 1-Boc-piperazine (912 mg, 4.9 mmol) and DIPEA (2.33 mL, 13.4 mmol). The resulting solution was stirred at room temperature for 25 hours, saturated aqueous NaHCO ₃ solution (75 mL) was added, and the resulting mixture was extracted with DCM. The organic layer was separated, washed successively with water (twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-7% MeOH) to give tert-butyl 4- (2-amino-6-bromo-5-chloronicotinoyyl) piperazine-1-carboxylate: ¹ H. NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (s, 1H), 6.66 (s, 2H), 3.33 (s, 8H), 1.40 (s, 9H). m / z (ESI, + ve) 419.0 (M + H) ⁺ .

Step 3: tert-butyl 4- (2-amino-6-bromo-5-chloropyridin-3-carbonoti oil) piperazine-1-carboxylate.
Lawesson's reagent (353 mg, 0.87 mmol) in THF (7. 2-amino-6-bromo-5-chloronicotinoyyl) piperazine-1-carboxylate tert-butyl (610 mg, 1.45 mmol). 5 mL), and the resulting solution was stirred at 50 ° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and treated sequentially with water (10 mL) and 1N HCl aqueous solution (4 mL). The resulting mixture was extracted with EtOAc (twice), the mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-6% MeOH) to give tert-butyl 4- (2-amino-6-bromo-5-chloropyridin-3-carbonothio oil) piperazin-1-carboxylate. Obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (s, 1H), 6.58 (br. S, 2H), 4.30 (ddd, J = 13.3, 6. 3, 3.3 Hz, 1H) 4.01-4.13 (m, 2H), 3.68-3.77 (m, 1H), 3.51-3.59 (m, 1H), 3 .40-3.50 (m, 3H), 1.41 (s, 9H). m / z (ESI, + ve) 434.9 (M + H) ⁺ .

Step 4: 4- (5,6-dichloroisothiazolo [3,4-b] pyridin-3-yl) piperazine-1-carboxylate tert-butyl.
NCS (116 mg, 0.87 mmol) in THF with 4- (2-amino-6-bromo-5-chloropyridin-3-carbonotioil) piperazine-1-carboxylate tert-butyl (343 mg, 0.79 mmol) It was added to the solution (8 mL) and the resulting solution was stirred at room temperature for 20 minutes. Then a mixture of water (10 mL) and 1M aqueous sodium sulfite solution (5 mL) was added and the resulting mixture was extracted with EtOAc (twice). The mixed extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-4% MeOH) and tert-butyl 4- (5,6-dichloroisothiazolo [3,4-b] pyridin-3-yl) piperazin-1-carboxylate. Obtained: ¹ H NMR (400 MHz, chloroform-d) δ 8.10 (s, 1H) 3.69-3.80 (m, 4H), 3.50-3.57 (m, 4H) , 1.51 (s, 9H). m / z (ESI, + ve) 389.0 (M + H) ⁺ .

Step 5: tert-butyl 4- (5-chloro-6- (3-methoxynaphthalene-1-yl) isothiazolo [3,4-b] pyridin-3-yl) piperazine-1-carboxylate.
4- (5,6-dichloroisothiazolo [3,4-b] pyridin-3-yl) piperazin-1-carboxylate tert-butyl (154 mg, 0.36 mmol), (3-methoxynaphthalene-1-yl) After blowing argon into a mixture of 1,4-dioxane solution (8 mL) and water (2 mL) in which a mixture of boronic acid (287 mg, 1.42 mmol) and cesium carbonate (463 mg, 1.42 mmol) was dissolved. Tetrakis (triphenylphosphine) palladium (41 mg, 0.04 mmol) was added. Argon was blown into the reaction mixture again, and then heated at 100 ° C. for 25 hours in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with saline (40 mL) and extracted with EtOAc (twice). The mixed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-3.5% MeOH) and 4- (5-chloro-6- (3-methoxynaphthalene-1-yl) isothiazolo [3,4-b] pyridine-3. -Il) Piperazine-1-carboxylate tert-butyl was obtained: m / z (ESI, + ve) 511.1 (M + H) ⁺ .

Step 6: 5-Chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) isothiazolo [3,4-b] pyridine.
Trifluoroacetic acid (560 μL, 7.6 mmol), 4- (5-chloro-6- (3-methoxynaphthalene-1-yl) isothiazolo [3,4-b] pyridin-3-yl) piperazin-1-carboxylic acid It was added to a DCM solution (6 mL) of tert-butyl acid (155 mg, 0.30 mmol) and the resulting solution was stirred at room temperature for 2.3 hours and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-25% MeOH) and 5-chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazin-1-yl) isothiazolo [3,4- b] Pyridine was given as a TFA salt: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7. 46-7.53 (m, 2H), 7.31 (d, J = 3.7 Hz, 2H), 7.19 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H) ), 3.76-3.83 (m, 4H), 3.35-3.43 (m, 4H). m / z (ESI, + ve) 411.0 (M + H) ⁺ .

Step 7: 1- (4- (5-Chloro-6- (3-methoxy-1-naphthalenyl) [1,2] thiazolo [3,4-b] pyridin-3-yl) -1-piperazinyl) -2 -Propene-1-on.
DCM of ice-cooled 5-chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) isothiazolo [3,4-b] pyridine (TFA salt; 100 mg, 0.19 mmol) DIPEA (100 μL, 0.57 mmol) and acryloyl chloride (23 μL, 0.29 mmol) were sequentially added to the slurry (5 mL). The resulting solution was stirred at 0 ° C. for 70 minutes and saturated aqueous NaHCO ₃ solution (15 mL) was added. The resulting mixture was extracted with DCM (3 times), the mixed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-7% MeOH) and 1- (4- (5-chloro-6- (3-methoxy-1-naphthalenyl) [1,2] thiazolo [3,4-]. b] Silica gel-3-yl) -1-piperazinyl) -2-propen-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 7.93. (D, J = 8.2 Hz, 1H), 7.45-7.54 (m, 2H), 7.25-7.39 (m, 2H), 7.19 (d, J = 2.5) Hz, 1H), 6.86 (dd, J = 16.7, 10.3 Hz, 1H), 6.19 (dd, J = 16.7, 2.3 Hz, 1H), 5.77 (dd) , J = 10.5, 2.3 Hz, 1H), 3.94 (s, 3H), 3.81-3.94 (m, 4H), 3.69-3.76 (m, 4H). m / z (ESI, + ve) 465.0 (M + H) ⁺ .

Step 8: 1- (4- (5-chloro-6- (3-hydroxy-1-naphthalenyl) [1,2] thiazolo [3,4-b] pyridin-3-yl) -1-piperazinyl) -2 -Propene-1-on.
Boron tribromide (1.0 M hexane solution, 400 μL, 0.40 mmol) with 1- (4- (5-chloro-6- (3-methoxynaphthalene-1-yl) isothiazolo [3,4-b] pyridine- 3-Il) Piperazine-1-yl) Propa-2-ene-1-one (37.3 mg, 0.08 mmol) was added (dripping) to an ice-cooled 1,2-dichloroethane solution (4 mL) to obtain the product. The mixture was stirred at 0 ° C. for 2.3 hours. Then, saturated aqueous NaHCO ₃ solution (5 mL) was added, and the obtained mixture was extracted with DCM: MeOH (4: 1) (twice). The mixed extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, DCM containing 0-6% MeOH) and 1- (4- (5-chloro-6- (3-hydroxy-1-naphthalenyl) [1,2] thiazolo [3,4-]. b] Pyridin-3-yl) -1-piperazinyl) -2-propen-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (br. S, 1H), 8 .72 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.17-7.28 (m, 3H), 7.09 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.19 (dd, J = 16.7) , 2.3 Hz, 1H), 5.74-5.79 (m, 1H), 3.81-3.95 (m, 4H), 3.68-3.76 (m, 4H). m / z (ESI, + ve) 451.0 (M + H) ⁺ .

ステップ１：１−（４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン。
０．２Ｍ塩化アクリロイルのＤＣＭ溶液（１．２４０ｍＬ、０．２４８ｍｍｏｌ）を、６−ブロモ−５−クロロ−７−フルオロ−３−（ピペラジン−１−イル）ベンゾ［ｃ］イソチアゾール（中間体Ｄ、８７ｍｇ、０．２４８ｍｍｏｌ）及びＮ，Ｎ−ジイソプロピルエチルアミン（０．１２９ｍＬ、０．７４４ｍｍｏｌ）の氷冷したジクロロメタン溶液（２．３ｍＬ）に加え、得られた混合物を０℃で１０分間撹拌した。その後、混合物を減圧濃縮し、残渣をＭｅＯＨ（２ｍＬ）中で超音波処理した。懸濁固体をろ別して回収し、ＭｅＯＨで洗浄してから真空乾燥させ、１−（４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）プロパ−２−エン−１−オンを得た：^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ８．１３ （１Ｈ、ｄ、Ｊ ＝ １．５６ Ｈｚ）、６．８４ （１Ｈ、ｄｄ、Ｊ ＝ １０．４７、１６．７３ Ｈｚ）、６．１７ （１Ｈ、ｄｄ、Ｊ ＝ ２．３５、１６．６３ Ｈｚ）、５．６６−５．８２ （１Ｈ、ｍ）、３．７３−３．９３ （４Ｈ、ｍ）、３．５５−３．６７ （４Ｈ、ｍ）。^１９Ｆ ＮＭＲ （３７６ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ −１１３．３９ （ｓ、１Ｆ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４０５．８ （Ｍ＋Ｈ）^＋。 Method 3
Examples 3-1: 1- (4- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa -2-en-1-on

Step 1: 1- (4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2-ene-1-one.
A solution of 0.2M acryloyl chloride in DCM (1.240 mL, 0.248 mmol) was added to 6-bromo-5-chloro-7-fluoro-3- (piperazine-1-yl) benzo [c] isothiazole (intermediate D). , 87 mg, 0.248 mmol) and N, N-diisopropylethylamine (0.129 mL, 0.744 mmol) in an ice-cooled dichloromethane solution (2.3 mL), and the resulting mixture was stirred at 0 ° C. for 10 minutes. The mixture was then concentrated under reduced pressure and the residue was sonicated in MeOH (2 mL). Suspended solids are collected by filtration, washed with MeOH and then vacuum dried to 1- (4- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1. -Il) Propa-2-en-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (1H, d, J = 1.56 Hz), 6.84 (1H). , Dd, J = 10.47, 16.73 Hz), 6.17 (1H, dd, J = 2.35, 16.63 Hz), 5.66-5.82 (1H, m), 3. 73-3.93 (4H, m), 3.55-3.67 (4H, m). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.39 (s, 1F). m / z (ESI, + ve) 405.8 (M + H) ⁺ .

Step 2: 1- (4- (5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2- En-1-on (intermediate E).
1- (4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2-ene-1-one (intermediate D, 79 mg, 0.20 mmol), (3-methoxynaphthalen-1-yl) boronic acid (47.3 mg, 0.234 mmol), tetrakis (triphenylphosphine) palladium (22.5 mg, 0.020 mmol), and sodium carbonate (83 mg, A mixture of water (0.500 mL) in which a mixture of 0.78 mmol) was dissolved and 1,4-dioxane (2.0 mL) was heated at 100 ° C. for 16 hours. Then, the reaction mixture is adsorbed on silica gel, purified by chromatography (silica gel, DCM containing 0 to 3% MeOH), and 1- (4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-)). Il) Benzo [c] isothiazole-3-yl) Piperazine-1-yl) Propa-2-en-1-one was obtained: m / z (ESI, + ve) 482.0 (M + H) ⁺ .

Step 3: 1- (4- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2- En-1-on.
Boron tribromide (1.0 M hexane solution, 0.664 mL, 0.664 mmol) was added to 1- (4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl)) benzo [c. ] Isothiazole-3-yl) piperazine-1-yl) propa-2-ene-1-one (64 mg, 0.13 mmol) added to an ice-cooled 1,2-dichloroethane solution (2.0 mL) to obtain The mixture was stirred at 0 ° C. for 1 hour. The reaction mixture was then added to saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and the resulting mixture was extracted with DCM: MeOH (2: 1) (10 mL). The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, DCM containing 0-3% MeOH) and 1- (4- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole). −3-Il) Piperazin-1-yl) Propa-2-en-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90-10.04 (1 H, m) , 8.10 (1H, s), 7.80 (1H, d, J = 8.41 Hz), 7.43 (1H, ddd, J = 1.96, 6.11, 8.17 Hz), 7.16-7.31 (3H, m), 7.07 (1H, d, J = 2.35 Hz), 6.87 (1H, dd, J = 10.47, 16.73 Hz), 6 .19 (1H, dd, J = 2.25, 16.73 Hz) 5.77 (1H, dd, J = 2.25, 10.47 Hz) 3.88 (4H, br d, J = 19.56 Hz), 3.61-3.72 (4H, m). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-123.78 (s, 1F). m / z (ESI, + ve) 468.0 (M + H) ⁺ .

１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン（中間体Ｅ、代替的合成法）：
６−ブロモ−３，５−ジクロロ−７−フルオロベンゾ［ｃ］イソチアゾール（中間体Ｃ、７１５ｍｇ、２．３７ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド溶液（５．６ｍＬ）に、１−（ピペラジン−１−イル）プロパ−２−エン−１−オン−ビス（２，２，２−トリフルオロアセタート）（９６１ｍｇ、２．６１ｍｍｏｌ、ｅＮｏｖａｔｉｏｎ Ｃｈｅｍｉｃａｌｓ ＬＬＣ、Ｂｒｉｄｇｅｗａｔｅｒ、ＮＪ、ＵＳＡ）のＮ，Ｎ−ジメチルホルムアミド溶液（５．６ｍＬ）及びＮ，Ｎ−ジイソプロピルエチルアミン（１．２４３ｍＬ、７．１２ｍｍｏｌ）を順次加えた。得られた混合物を室温で１時間撹拌し、その後、５０℃で２２時間加熱した。室温に冷却した後、反応混合物を氷水（１０ｍＬ）に加え、生じた析出物をろ過によって回収し、水で洗浄した。回収した固体をシリカゲルに吸着させ、クロマトグラフィー（シリカゲル、ＭｅＯＨ０〜３％含有ＤＣＭ）で精製し、１−（４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）プロパ−２−エン−１−オンを与えた。

Alternative synthesis of intermediate E

1- (4- (5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2-ene-1 -On (Intermediate E, alternative synthesis method):
1- (Piperazine-) in a solution of 6-bromo-3,5-dichloro-7-fluorobenzo [c] isothiazole (intermediate C, 715 mg, 2.37 mmol) in N, N-dimethylformamide (5.6 mL). 1-yl) Propa-2-en-1-on-bis (2,2,2-trifluoroacetate) (961 mg, 2.61 mmol, eNovation Chemicals LLC, Bridgewater, NJ, USA) N, N-dimethyl A formamide solution (5.6 mL) and N, N-diisopropylethylamine (1.243 mL, 7.12 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 1 hour and then heated at 50 ° C. for 22 hours. After cooling to room temperature, the reaction mixture was added to ice water (10 mL) and the resulting precipitate was collected by filtration and washed with water. The recovered solid is adsorbed on silica gel, purified by chromatography (silica gel, DCM containing 0 to 3% MeOH), and 1- (4- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3). -Il) piperazine-1-yl) propa-2-en-1-one was given.

ステップ１：６−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）−２，６−ジアザスピロ［３．３］ヘプタン−２−カルボン酸ｔｅｒｔ−ブチル。
６−ブロモ−３，５−ジクロロ−７−フルオロベンゾ［ｃ］イソチアゾール（中間体Ｃ、１６９ｍｇ、０．５６２ｍｍｏｌ）と２−Ｂｏｃ−２，６−ジアザスピロ［３．３］ヘプタン（２１２ｍｇ、１．０７ｍｍｏｌ、ＡｓｔａＴｅｃｈ，Ｉｎｃ．、Ｂｒｉｓｔｏｌ、ＰＡ、ＵＳＡ）との混合ＤＭＦ溶液（３．５ｍＬ）を室温で５時間撹拌した。氷水（５ｍＬ）を加え、得られた混合物を１５分間撹拌した。生じた析出物をろ過によって回収し、水で洗浄してから真空乾燥させ、６−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）−２，６−ジアザスピロ［３．３］ヘプタン−２−カルボン酸ｔｅｒｔ−ブチルを得た：^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ７．５２−７．７４ （１ Ｈ、ｍ）、４．５５ （４ Ｈ、ｓ）、４．０９ （４ Ｈ、ｓ）、１．３８ （９ Ｈ、ｓ）。 ^１９Ｆ ＮＭＲ （３７６ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ −１１３．５５ （１Ｆ、ｓ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４６４．０ （Ｍ＋１）。 Method 4
Examples 4-1: 1- (6- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) -2,6-diazaspiro [ 3.3] Heptane-2-yl) propa-2-en-1-one.

Step 1: 6- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] tert-butyl heptane-2-carboxylate.
6-Bromo-3,5-dichloro-7-fluorobenzo [c] isothiazole (Intermediate C, 169 mg, 0.562 mmol) and 2-Boc-2,6-diazaspiro [3.3] heptane (212 mg, 1) A mixed DMF solution (3.5 mL) with .07 mmol, AstaTech, Inc., Bristol, PA, USA) was stirred at room temperature for 5 hours. Ice water (5 mL) was added and the resulting mixture was stirred for 15 minutes. The resulting precipitate is collected by filtration, washed with water and then vacuum dried to 6- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) -2,6- Diazaspiro [3.3] tert-butyl heptane-2-carboxylate was obtained: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.52-7.74 (1 H, m), 4.55 ( 4 H, s), 4.09 (4 H, s), 1.38 (9 H, s). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.55 (1F, s). m / z (ESI, + ve) 464.0 (M + 1).

Step 2: 1- (6- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] heptane-2-yl) propa 2-en-1-on.
Hydrogen chloride solution (4M, 1,4-dioxane solution, 5.0 mL, 20 mmol), 6- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) -2,6 -Diazaspiro [3.3] tert-butyl heptane-2-carboxylate (249 mg, 0.538 mmol) was added to a methanol solution (10 mL) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to give 6-bromo-5-chloro-7-fluoro-3- (2,6-diazaspiro [3.3] heptane-2-yl) benzo [c] isothiazole: m / z (ESI, + ve) 363.8 (M + 1) ⁺ .

A dichloromethane solution (3.0 mL) of N, N-diisopropylethylamine (0.281 mL, 1.61 mmol) was added to this material, and the resulting mixture was cooled to 0 ° C. Then acryloyl chloride (0.2 M DCM solution, 2.69 mL, 0.538 mmol) was added and the resulting mixture was stirred at 0 ° C. for 10 minutes. The reaction mixture was then concentrated under reduced pressure and the residue was purified by chromatography (silica gel, DCM with EtOAc / EtOH (3: 1) 0-10%) 1- (6- (6-bromo-5-chloro-7). -Fluorobenzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] heptane-2-yl) propa-2-ene-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65 (1 H, d, J = 1.4 Hz), 6.25-6.36 (1 H, m), 6.10 (1 H, dd, J = 17. 0, 2.3 Hz), 5.64-5.72 (1 H, m), 4.58 (4 H, s), 4.47 (2 H, s), 4.18 (2 H, s) ). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.54 (1F, s). m / z (ESI, + ve) 418.0 (M + H) ⁺ .

Step 3: 1- (6- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] ] Heptane-2-yl) propa-2-en-1-one.
1- (6- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] heptan-2-yl) propa-2-ene -1-one (102 mg, 0.245 mmol), (3-methoxynaphthalene-1-yl) boronic acid (59.3 mg, 0.294 mmol), tetrakis (triphenylphosphine) palladium (28.3 mg, 0.024 mmol) , And a mixture of water (0.5 mL) in which a mixture of sodium carbonate (104 mg, 0.979 mmol) was dissolved and 1,4-dioxane (2.0 mL) was heated at 100 ° C. for 1 hour. Then, the reaction mixture was adsorbed on silica gel and purified by chromatography (silica gel, DCM containing 0 to 5% MeOH). The purified substance was ultrasonically treated in MeOH, the suspended solid was collected by filtration, washed with MeOH and then vacuum dried to 1- (6- (5-chloro-7-fluoro-6- (3-). Methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] heptane-2-yl) propa-2-ene-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (1 H, d, J = 8.4 Hz), 7.67 (1 H, s), 7.45-7.57 (2 H, m) ), 7.23-7.36 (2 H, m), 7.16 (1 H, d, J = 2.5 Hz), 6.27-6.39 (1 H, m), 6.11 (1 H, dd, J = 17.0, 2.2 Hz) 5.65-5.76 (1 H, m), 4.58-4.67 (4 H, m), 4.50 ( 2 H, s), 4.22 (2 H, s), 3.93 (3 H, s). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-123.88 (1F, s). m / z (ESI, + ve) 494.0 (M + H) ⁺ .

Step 4: 1- (6- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] ] Heptane-2-yl) Propa-2-en-1-one.
Boron tribromide (1.0 M hexane solution, 0.638 mL, 0.638 mmol) was added to 1- (6- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl)) benzo [c. ] Isothiazole-3-yl) -2,6-diazaspiro [3.3] heptane-2-yl) propa-2-ene-1-one (63 mg, 0.128 mmol) ice-cooled 1,2-dichloroethane It was added to the solution (2.0 mL) and the resulting mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was then added to saturated aqueous sodium hydrogen carbonate solution (2.0 mL) and the resulting mixture was extracted with DCM: MeOH (2: 1) (10 mL). The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, MeOH (containing 2M ammonia) 0 to 2% DCM) and 1- (6- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl)). Benzo [c] isothiazole-3-yl) -2,6-diazaspiro [3.3] heptan-2-yl) propa-2-en-1-one was obtained: ¹ H NMR (400 MHz, DMSO). -D ₆ ) δ 9.82-10.04 (1 H, m), 7.79 (1 H, d, J = 8.2 Hz), 7.66 (1 H, s), 7.43 ( 1 H, dt, J = 8.3, 4.0 Hz), 7.26 (1 H, d, J = 2.3 Hz), 7.22 (2 H, d, J = 3.7 Hz) , 7.05 (1 H, d, J = 2.3 Hz), 6.26-6.38 (1 H, m), 6.12 (1 H, dd, J = 16.8, 2.2) Hz) 5.66-5.72 (1 H, m), 4.58-4.67 (4 H, m), 4.50 (2 H, s), 4.22 (2 H, s) .. ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-123.98 (1F, s). m / z (ESI, + ve) 480.0 (M + H) ⁺ .

ステップ１：２−アミノ−５−クロロ−３−フルオロ−４−（３−メトキシナフタレン−１−イル）ベンズアミド。
（３−メトキシナフタレン−１−イル）ボロン酸（２．０４ｇ、１０．１ｍｍｏｌ）、２−アミノ−４−ブロモ−５−クロロ−３−フルオロベンズアミド（中間体Ｂ（１．９３ｇ、７．２０ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０．８３２ｇ、０．７２０ｍｍｏｌ）、炭酸ナトリウム（１．２ｍＬ、２８．８ｍｍｏｌ）を溶解させた水溶液（９．６ｍＬ）と、１，４−ジオキサン溶液（３８．４ｍＬ）との混合液を９０℃で２日間加熱した。その後、反応混合物をセライトパッドに通してろ過し、ＥｔＯＡｃで洗浄した。ろ液を飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）で希釈し、ＥｔＯＡｃで抽出した（５０ｍＬ、３回）。有機抽出物を食塩水（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。その後、溶液をろ過し、ろ液を減圧濃縮した。残渣をＭｅＯＨ（５ｍＬ）に懸濁させ、懸濁固体をろ別して回収してＭｅＯＨで洗浄してから乾燥させ、２−アミノ−５−クロロ−３−フルオロ−４−（３−メトキシナフタレン−１−イル）ベンズアミドが得られた。濃縮したろ液をクロマトグラフィー（シリカゲル、ＥｔＯＡｃ−ＥｔＯＨ（３：１）０％〜１００％含有ヘプタン）で精製し、さらなる２−アミノ−５−クロロ−３−フルオロ−４−（３−メトキシナフタレン−１−イル）ベンズアミドを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ８．０１ − ８．１７ （ｍ、１Ｈ）、７．９２ （ｄ、Ｊ ＝ ８．２ Ｈｚ、１Ｈ）、７．７５ （ｓ、１Ｈ）、７．４３ − ７．５５ （ｍ、３Ｈ）、７．２３ − ７．３４ （ｍ、２Ｈ）、７．１０ （ｄ、Ｊ ＝ ２．５ Ｈｚ、１Ｈ）、６．７３ （ｓ、２Ｈ）、３．９３ （ｓ、３Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ３４５．０ （Ｍ＋Ｈ）^＋。 Method 5
Examples 5-1: N- (1- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -3-azetidinyl) -N − Methyl-2-propeneamide

Step 1: 2-Amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzamide.
(3-Methoxynaphthalene-1-yl) boronic acid (2.04 g, 10.1 mmol), 2-amino-4-bromo-5-chloro-3-fluorobenzamide (intermediate B (1.93 g, 7.20 mmol) ), Tetrax (triphenylphosphine) palladium (0.832 g, 0.720 mmol), sodium carbonate (1.2 mL, 28.8 mmol) dissolved aqueous solution (9.6 mL), and 1,4-dioxane solution (38). The mixture with (.4 mL) was heated at 90 ° C. for 2 days. The reaction mixture was then filtered through a Celite pad and washed with EtOAc. The filtrate was diluted with saturated aqueous NaHCO ₃ solution (50 mL) and with EtOAc. Extracted (50 mL, 3 times). The organic extract was washed with saline (30 mL) and dried over Na ₂ SO _{4. The} solution was then filtered and the filtrate was concentrated under reduced pressure. The residue was MeOH (5 mL). ), The suspended solid is collected by filtration, washed with MeOH, and dried to obtain 2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzamide. The resulting concentrated filtrate was purified by chromatography (silica, EtOAc-EtOH (3: 1) 0% -100% heptan) and further 2-amino-5-chloro-3-fluoro-4- (). 3-Methoxynaphthalene-1-yl) benzamide was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01-8.17 (m, 1H), 7.92 (d, J = 8. 2 Hz, 1H), 7.75 (s, 1H), 7.43-7.55 (m, 3H), 7.23-7.34 (m, 2H), 7.10 (d, J = 2) .5 Hz, 1H), 6.73 (s, 2H), 3.93 (s, 3H). M / z (ESI, + ve) 345.0 (M + H) ⁺ .

Step 2: 2-Amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzothioamide.
Lawesson's reagent (1.49 mL, 3.) in a tetrahydrofuran solution (41 mL) of 2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzamide (2.11 g, 6.12 mmol). 67 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with EtOAc (60 mL) and washed successively with 2M HCl (60 mL), saturated aqueous NaHCO ₃ solution (60 mL) and saline (60 mL). The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was sonicated in DCM (5 mL), the resulting precipitate was collected by filtration, washed with DCM and then vacuum dried to 2-amino-5-chloro-3-fluoro-4- (3-). Methoxynaphthalene-1-yl) benzothioamide was obtained. The filtrate is purified by chromatography (silica gel, EtOAc-EtOH (3: 1) 0% -100% heptan) and further 2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1). -Il) Benzothioamide was obtained: m / z (ESI, + ve) 361.0 (M + H) ⁺ .

Step 3: 5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-amine.
A hydrogen peroxide solution (30% aqueous solution, 2.2 mL, 21.3 mmol) was added to 2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzothioamide (1.92 g, 5). It was added slowly to an ice-cold pyridine solution (18 mL) of .33 mmol). The resulting mixture was warmed to room temperature and stirred at room temperature for 18 hours. Then, the reaction mixture is diluted with water (60 mL), the resulting precipitate is collected by filtration, washed with water and MeOH in that order, and then vacuum dried, and 5-chloro-7-fluoro-6- (3-methoxy) is used. Naphthalene-1-yl) benzo [c] isothiazole-3-amine was obtained: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (s, 2H), 7.99-8.03 (M, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.48-7.55 (m, 1H), 7.47 (d, J = 2.3 Hz, 1H) , 7.31 (d, J = 3.9 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-124.71 (s, 1F). m / z (ESI, + ve) 359.0 (M + H) ⁺ .

Step 4: 3,5-Dichloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole.
5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-amine (1.55 g, 4.31 mmol), copper (II) chloride (0.870 g) , 6.47 mmol) and tert-butyl nitrite (0.77 mL, 6.47 mmol) in acetonitrile suspension (43 mL) at 65 ° C. over 15 minutes in small portions. The resulting mixture was stirred at 65 ° C. for 30 minutes, then cooled to room temperature and diluted with ice water (50 mL). The precipitated solid was collected by filtration, washed with water, and vacuum dried. The residue was sonicated in DCM (10 mL), the suspended solid was filtered and collected, washed with DCM, vacuum dried and unreacted 5-chloro-7-fluoro-6- (3-methoxynaphthalene-). 1-Il) Benzo [c] isothiazole-3-amine was recovered. The filtrate was concentrated under reduced pressure to give 3,5-dichloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.49-7.56 (m, 2H) , 7.28-7.36 (m, 2H), 7.24-7.28 (m, 1H), 3.95 (s, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-122.17 (s, 1F). m / z (ESI, + ve) 378.0 (M + H) ⁺ .

Step 5: (1- (5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) azetidine-3-yl) (methyl) carbamic acid tert -Butyl.
3,5-Dichloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole (100 mg, 0.264 mmol), DIPEA (0.14 mL, 0.793 mmol), and 3- A mixed DMF solution (1.3 mL) of Boc-3-methylaminoazatidine (0.098 mL, 0.529 mmol, Beta Pharma Scientific, Inc.) was stirred at room temperature for 18 hours. Then ice water (3 mL) was added and the resulting mixture was stirred for 15 minutes. Then, the precipitated solid is collected by filtration, washed with water, and dried under vacuum (1- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole). −3-Il) Azetidine-3-yl) (methyl) tert-butyl carbamate was given: m / z (ESI, + ve) 528.0 (M + H) ⁺ .

Step 6: N- (1- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -3-azetidinyl) -N-methyl- 2-Propenamide.
The title compound was subjected to (1- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-3) according to the procedure reported in Method 1, Step 8. Prepared from tert-butyl (131.1 mg, 0.248 mmol) of azetidine-3-yl) (methyl) carbamate in 3 steps: ¹ Hz NMR (400 MHz, DMSO-d ₆ ) δ 9.89-10. .10 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.43 (ddd, J = 8.2, 5.1, 2) 9.9 Hz, 1H), 7.20-7.30 (m, 3H), 7.05 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 16.7, 10. 5 Hz, 1H), 6.10-6.23 (m, 1H), 5.69-5.81 (m, 1H), 5.37-5.59 (m, 1H), 4.63-4 .74 (m, 3H), 4.53-4.61 (m, 1H), 3.14-3.23 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-124.10 (s, 1F). m / z (ESI, + ve) 468.0 (M + H) ⁺ .

ステップ１：４−（５−クロロ−７−フルオロ−６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｄ、１．１０ｇ、２．４５ｍｍｏｌ）、ビス（ピナコラト）ジボロン（１．８６ｇ、７．３４ｍｍｏｌ）、酢酸カリウム（０．６１ｍＬ、９．８ｍｍｏｌ）、及びＰｄ（ｄｐｐｆ）Ｃｌ_２・ＤＣＭ（０．５３７ｇ、０．７３４ｍｍｏｌ）の混合物の１，４−ジオキサン溶液（１２ｍＬ）を１００℃で４０時間加熱した。その後、反応混合物を減圧濃縮してクロマトグラフィー（シリカゲル、ＥｔＯＡｃ−ＥｔＯＨ（３：１）０％〜１００％含有ヘプタン）で精製し、４−（５−クロロ−７−フルオロ−６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た：^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ７．８５ （ｓ、１Ｈ）、３．５９ （ｂｒ ｄ、Ｊ ＝ ４．７ Ｈｚ、４Ｈ）、３．４４ − ３．５４ （ｍ、４Ｈ）、１．４３ （ｓ、９Ｈ）、１．３５ （ｓ、５Ｈ）、１．１５ （ｓ、７Ｈ）。 ^１９Ｆ ＮＭＲ （３７６ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ −１２５．１１ （ｓ、１Ｆ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４９８．０ （Ｍ＋Ｈ）^＋。 Method 6
Examples 6-1: 1- (4- (6- (6-amino-3-chloro-2-pyridinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1- Piperazinyl) -2-propene-1-one

Step 1: 4- (5-Chloro-7-fluoro-6- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [c] isothiazole-3-yl ) Piperazine-1-carboxylate tert-butyl.
4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (intermediate D, 1.10 g, 2.45 mmol), bis ( pinacolato) diboron (1.86 g, 7.34 mmol), potassium acetate (0.61 mL, 9.8 mmol), and _{Pd (dppf) Cl 2 · DCM} (0.537g, of a mixture of 0.734 mmol) 1,4 The dioxane solution (12 mL) was heated at 100 ° C. for 40 hours. The reaction mixture is then concentrated under reduced pressure and purified by chromatography (silica gel, EtOAc-EtOH (3: 1) 0% -100% hertz) and 4- (5-chloro-7-fluoro-6- (4,). 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl was obtained: ¹ H NMR (400). MHz, DMSO-d ₆ ) δ 7.85 (s, 1H), 3.59 (br d, J = 4.7 Hz, 4H) 3.44 − 3.54 (m, 4H), 1.43 (S, 9H), 1.35 (s, 5H), 1.15 (s, 7H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-125.11 (s, 1F). m / z (ESI, + ve) 498.0 (M + H) ⁺ .

Step 2: 4- (6- (6-amino-3-chloropyridin-2-yl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl ..
4- (5-Chloro-7-fluoro-6- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzo [c] isothiazole-3-yl) piperazine- Tert-butyl 1-carboxylic acid (99.5 mg, 0.200 mmol), SPhos Pd G3 (17.3 mg, 0.020 mmol), 6-bromo-5-chloropyridin-2-amine (Combi-blocks Inc., San) A mixed solution of an aqueous solution (0.25 mL) in which a mixture of Diego, CA, USA, 124 mg, 0.6 mmol) and sodium carbonate (85 mg, 0.80 mmol) is dissolved and 1,2-DCE (0.75 mL). Was heated at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography (silica gel, EtOAc-EtOH (3: 1) 0% to 100% heptan) and 4- (6- (6-amino-3-chloropyridin-2-yl). )-5-Chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl was obtained: m / z (ESI, + ve) 498.0 (M + H) ⁺ .

Step 3: 1- (4- (6- (6-amino-3-chloro-2-pyridinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl)- 2-Propene-1-on.
The title compound, 4-(6- (6-amino-3-chloropyridine-2-yl) -5-chloro-7-fluorobenzo [c] isothiazole, according to the procedure reported in Method 1, Step 8. -3-yl) Prepared from tert-butyl piperazin-1-carboxylate (31.6 mg, 0.063 mmol) in 2 steps: ¹ Hz NMR (400 MHz, DMSO-d ₆ ) δ 7.97-8.10 (M, 1H), 7.60 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 16.6, 10.6 Hz, 1H), 6.57 (d, J = 8.9 Hz, 1H), 6.38 (s, 2H), 6.19 (dd, J = 16.8, 2.3 Hz, 1H), 5.71-5.84 (m, 1H), 3.86 (br d, J = 19.9 Hz, 4H), 3.63 (br d, J = 1.0 Hz, 4H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-126.04 (s, 1F). m / z (ESI, + ve) 452.0 (M + H) ⁺ .

ステップ１：２−アミノ−５−クロロ−３−フルオロ−４−（３−メトキシナフタレン−１−イル）安息香酸。
方法１、ステップ７に記載の手順と同様の手順を使用して中間体Ａから調製した：ｍ／ｚ （ＥＳＩ、＋ｖｅ） ３４６．０ （Ｍ＋Ｈ）^＋。 Method 7
Examples 7-1: 1-((3R) -4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -3-yl) (Difluoromethyl) -1-piperazinyl) -2-propen-1-one | 1-((3S) -4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2, 1-Benzothiazole-3-yl) -3- (difluoromethyl) -1-piperazinyl) -2-propen-1-one

Step 1: 2-Amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzoic acid.
Prepared from Intermediate A using the same procedure as described in Method 1, Step 7: m / z (ESI, + ve) 346.0 (M + H) ⁺ .

Step 2: tert-butyl 4- (2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzoyl) -3- (difluoromethyl) piperazine-1-carboxylate.
2-Amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzoic acid (0.150 g, 0.434 mmol), TBTU (0.188 g, 0.586 mmol), 3- ( A DMF solution (4 mL) of a mixture of tert-butyl (0.123 g, 0.521 mmol) of difluoromethyl) piperazin-1-carboxylate and DIPEA (0.23 mL, 1.302 mmol) was stirred at room temperature for 3 hours. The reaction mixture was then washed with saturated aqueous NaHCO ₃ solution and the aqueous wash solution was extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, EtOAc 0-40% / heptane) and 4- (2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) benzoyl) -3-. Obtained tert-butyl (difluoromethyl) piperazin-1-carboxylate: m / z (ESI, + ve) 586 (M + Na) ⁺ .

Step 3: 4- (2-Amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) phenylcarbonoti oil) -3- (difluoromethyl) piperazine-1-carboxylic acid tert- Butyl.
Lawesson's reagent (0.041 mL, 0.10 mmol), 4- (2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalen-1-yl) benzoyl) -3- (difluoromethyl) piperazine It was added to a THF solution (4 mL) of tert-butyl-1-carboxylate (0.095 g, 0.168 mmol) and the resulting mixture was stirred at 50 ° C. for 18 hours. The reaction mixture is then concentrated under reduced pressure and purified by column chromatography (silica gel, EtOAc 0-30% / heptane) and 4- (2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1). -Il) phenylcarbonoti oil) -3- (difluoromethyl) piperazin-1-carboxylate tert-butyl was obtained: m / z (ESI, + ve) 602.2 (M + Na) ⁺ .

Step 4: 4- (5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) -3- (difluoromethyl) piperazine-1-carboxylic acid tert-butyl.
NBS (0.022 g, 0.17 mmol), 4- (2-amino-5-chloro-3-fluoro-4- (3-methoxynaphthalene-1-yl) phenylcarboxylic acid oil) -3- (difluoromethyl) ) It was added to a THF solution (7 mL) of tert-butyl piperazin-1-carboxylate, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water and washed with 10% sodium thiosulfate. After extracting the aqueous washing solution with EtOAc, the combined organic layers were concentrated under reduced pressure and 4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-3. Ill) -3- (difluoromethyl) piperazine-1-carboxylate tert-butyl was obtained: m / z (ESI, + ve) 578.2 (M + H) ⁺ .

Step 5: 1-((3R) -4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -3- (difluoromethyl) ) -1-Piperadinyl) -2-propen-1-one | 1-((3S) -4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzo Thiazole-3-yl) -3- (difluoromethyl) -1-piperazinyl) -2-propen-1-one.
Method 1, prepared using the same procedure as described in step 8: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (br. S., 1 H) 8.12 (d) , J = 2.2 Hz, 1 H) 7.80 (d, J = 8.2 Hz, 1 H) 7.43 (br t, J = 7.0 Hz, 1 H) 7.20-7. 30 (m, 3H) 7.08 (dd, J = 5.8, 2.2 Hz, 1H) 6.78-6.91 (m, 1H) 6.27-6.70 (m, 1 H) 6.20 (dd, J = 16.6, 2.0 Hz, 1 H) 5.76-5.84 (m, 1 H) 4.73-4.87 (m, 1 H) 4 .19-4.72 (m, 2H) 3.55-3.90 (m, 3H) 3.36-3.47 (m, 1H). m / z (ESI, + ve) 518.0 (M + H) ⁺ .

ステップ１：４−ブロモ−５−クロロ−２−フルオロベンズアミド。
４−ブロモ−５−クロロ−２−フルオロ安息香酸（２３．３ｇ、９２ｍｍｏｌ）を溶解させた塩化チオニル（６７ｍＬ、０．９２ｍｏｌ）の混合液を還流冷却器で７０℃にて１時間撹拌した。その後、反応混合物を減圧濃縮し、残渣を１，４−ジオキサン（２００ｍＬ）に取り、水酸化アンモニウム（３０％水溶液、８２ｍＬ、０．６４ｍｏｌ）で処理し、室温で１５分間撹拌した。反応混合物を減圧濃縮し、４−ブロモ−５−クロロ−２−フルオロベンズアミドが得られた：ｍ／ｚ （ＥＳＩ、＋ｖｅ） ２５１．８ （Ｍ＋Ｈ）^＋。 Method 8
Example 8-1: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2- (2-propanil) phenyl) -4- (4- (2-propenoyl) -1-piperazinyl) ) -2 (1H) -quinazolinone

Step 1: 4-Bromo-5-chloro-2-fluorobenzamide.
A mixed solution of thionyl chloride (67 mL, 0.92 mol) in which 4-bromo-5-chloro-2-fluorobenzoic acid (23.3 g, 92 mmol) was dissolved was stirred at 70 ° C. for 1 hour in a reflux condenser. Then, the reaction mixture was concentrated under reduced pressure, the residue was taken up in 1,4-dioxane (200 mL), treated with ammonium hydroxide (30% aqueous solution, 82 mL, 0.64 mol), and stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give 4-bromo-5-chloro-2-fluorobenzamide: m / z (ESI, + ve) 251.8 (M + H) ⁺ .

Step 2: 4-Bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl) carbamoyl) benzamide.
Reflux cooler with a mixed DCE solution (100 mL) of 4-bromo-5-chloro-2-fluorobenzamide (5.90 g, 23.4 mmol) and oxalyl chloride (1 M, DCM solution; 12.9 mL, 25.7 mmol). Was stirred at 80 ° C. for 1 hour. The reaction mixture was then cooled to room temperature and 2-isopropylaniline (6.62 mL, 46.7 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes and then cooled to 0 ° C. The precipitated solid was filtered off and the recovered filtrate was concentrated under reduced pressure to give 4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl) carbamoyl) benzamide: ¹ H. NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (br. S., 1H) 10.31 (s, 1H) 7.97-8.05 (m, 2H) 7.82 (d, J = 7.2 Hz, 1H) 7.32-7.38 (m, 1H) 7.14-7.25 (m, 2H) 3.11 (spt, J = 6.8 Hz, 1H) 1.24 ( d, J = 6.8 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.6 (s, 1 F). m / z (ESI, + ve) 412.7 and 414.6 (M + H) ⁺ .

Step 3: 7-Bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione (intermediate F).
KHMDS (1M THF solution, 8.30 mL, 8.30 mmol) in 4-bromo-5-chloro-2-fluoro-N-((2-isopropylphenyl) carbamoyl) benzamide (1.56 g, 3.77 mmol) It was added to a mixed THF solution (19 mL) at −20 ° C. and the resulting mixture was warmed to room temperature over 1 hour. The reaction mixture was then diluted with EtOAc (150 mL) and washed with saturated aqueous ammonium chloride solution (100 mL, twice). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was suspended in DCM (5 mL), ultrasonically treated, collected by filtration and then vacuum dried to 7-bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2,4 (1H,). .. 3H) - dione was ^{obtained: 1 H NMR (400 MHz,} CDCl 3) δ 9.43 (br s, 1H) 8.29 (s, 1H) 7.55 - 7.59 (m, 2H ) 7.39-7.44 (m, 1H) 7.16 (d, J = 7.8 Hz, 1H) 6.75 (s, 1H) 2.59-2.77 (m, 1H) 1. 17-1.24 (m, 3H) 1.11 (d, J = 6.8 Hz, 3H). m / z (ESI, + ve) 392.9 and 395.0 (M + H) ⁺ .

Step 4: 6-Chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione.
7-Bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione (intermediate F, 1.17 g, 2.96 mmol), (2-fluoro-6-methoxy) DME solution (30 mL) of a mixture of phenylboronic acid (2.02 g, 11.9 mmol), SPhos Pd G3 (0.128 g, 0.148 mmol), and potassium carbonate (2 M, aqueous solution 4.45 mL, 8.90 mmol). ) Was stirred at 85 ° C. for 16 hours. The reaction mixture was then diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO ₃ solution (100 mL, 3 times). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica, Hertz with 0-50% EtOAc) and 6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2,4 (1H). , 3H) - dione was ^{obtained: 1 H NMR (400 MHz,} DMSO-d 6) δ 11.90 (d, J = 1.2 Hz, 1H) 8.11 (d, J = 3.3 Hz , 1H) 7.53-7.59 (m, 1H) 7.48 (tt, J = 7.0, 2.2 Hz, 1H) 7.38-7.44 (m, 1H) 7.32 -7.37 (m, 2H) 6.93 (dd, J = 8.4, 4.3 Hz, 1H) 6.86 (t, J = 8.7 Hz, 1H) 6.15 (s, 1H) ) 3.66 (d, J = 30 Hz, 3H) 2.73 (dq, J = 14.2, 7.0 Hz, 1H) 1.11 (t, J = 7.1 Hz, 3H) 1. 03 (dd, J = 12.7, 6.8 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ-113.8 (s, 1F) -115.2 (s, 1F). m / z (ESI, + ve) 439.1 (M + H) ⁺ .

Step 5: 4,6-dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one.
6-Chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione (0.395 g, 0.900 mmol) and Et ₃ N Quinazoline (0.503 mL, 5.40 mmol) was added to an acetonitrile solution (9 mL) of (0.753 mL, 5.40 mmol), and the obtained solution was stirred at 80 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give 4,6-dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one: m / z. (ESI, + ve) 457.1 (M + H) ⁺ .

Alternative procedure of step 5 (used as noted in the table below): product obtained in step 4 (1.0 eq), triethylamine (18.0 eq), and 1H-benzo [d] [1, 2, 2, 3] Phosphorus oxychloride (6.0 eq) was added to a stirred mixture of triazole (12 eq) in acetonitrile (0.07 M) and the resulting reaction mixture was stirred at 80 ° C. for 3.5 hours. The reaction mixture was then slowly poured into water (100 mL) that was rapidly stirred at 10 ° C. The aqueous suspension was stirred for 15 minutes and then extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over sulfonyl ₄ and filtered, then concentrated under reduced pressure to give the benzotriazole adduct intermediate, which was used directly in step 6.

Step 6: 4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazine-1 -Tert-Butyl carboxylate.
4,6-Dichloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -on (obtained in method 8, step 5), piperazine- 1-carboxylic acid tert- butyl (0.335g, 1.80mmol), and was _{Et 3 N (0.753mL, 5.40mmol)} DCE solution of the (9 mL) was stirred at 60 ° C. 20 min. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO ₃ solution (75 mL, 3 times). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing 0 to 60% of EtOAc-EtOH (3: 1)) and 4- (6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2). -Isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazine-1-carboxylate tert-butyl was obtained: m / z (ESI, + ve) 607.3 (M + H) ⁺ .

Note: When (S) -1- (3-methylpiperazin-1-yl) propa-2-en-1-one 2,2,2-trifluoroacetate was used, it was synthesized as follows:

(S) -1- (3-Methylpiperazin-1-yl) propa-2-ene-1-one 2,2,2-trifluoroacetate

Step 6-a: 4-acryloyl-2-methylpiperazin-1-carboxylic acid (S) -tert-butyl.
Acryloyl chloride (1.34 mL, 16.5 mmol) in THF (30.0 mL) of (S) -1-boc-2-methyl-piperazine (3.00 g, 15.0 mmol, Boc Sciences, Shirley, NY) Was added at −10 ° C. and the resulting mixture was stirred at −10 ° C. for 5 minutes. Then, triethylamine (6.26 mL, 44.9 mmol) was slowly added, and the obtained mixture was stirred at −10 ° C. for 15 minutes and then warmed to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous layer was extracted with EtOAc (3 times), then the organic layers were combined, dried with acetate ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing 100% EtOAc 0 to 100%) to give 4-acryloyl-2-methylpiperazin-1-carboxylic acid (S) -tert-butyl: ¹ H NMR (400 MHz, DMSO). -D ₆ ) δ 6.72-6.85 (m, 1H) 6.10-6.18 (m, 1H) 5.68-5.76 (m, 1H) 4.08-4.32 (m) , 2H) 3.68-4.03 (m, 2H) 2.86-3.14 (m, 2H) 2.66-2.80 (m, 1H) 1.38-1.43 (s, 9H) ) 0.96-1.04 (m, 3H). m / z (ESI, + ve) 277.3 (M + Na) ⁺ .

Step 6-b: (S) -1- (3-methylpiperazin-1-yl) propa-2-ene-1-one 2,2,2-trifluoroacetate.
A mixed DCM solution (16 mL) of 4-acryloyl-2-methylpiperazine-1-carboxylic acid (S) -tert-butyl (3.21 g, 12.62 mmol) and TFA (4.7 mL, 63.1 mmol) at room temperature. Was stirred for 24 hours. The reaction mixture was then concentrated under reduced pressure to give (S) -1- (3-methylpiperazin-1-yl) propa-2-ene-1-one 2,2,2-trifluoroacetate: ¹ 1 H NMR (400 MHz, DMSO-d ₆ ) δ 8.70-8.99 (m, 1H) 6.74-6.91 (m, 1H) 6.12-6.26 (m, 1H) 5. 70-5.84 (m, 1H) 4.25-4.44 (m, 1H) 4.07-4.25 (m, 1H) 3.49-3.53 (m, 1H) 3.22- 3.32 (m, 2H) 2.92-3.08 (m, 2H) 1.14-1.29 (m, 3H). m / z (ESI, + ve) 155.1 (M + H) ⁺ .

Step 7: 6-Chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) -4- (piperazine-1-yl) quinazoline-2 (1H) -one.
4- (6-Chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazine-1-carboxylic acid A TFA solution (4 mL) of tert-butyl (0.594 g, 0.978 mmol) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to 6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) -4- (piperazine-1-yl) quinazoline-2 (1H) -one. Was obtained: m / z (ESI, + ve) 507.2 (M + H) ⁺ .

Step 8: 4- (4-Acryloylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one.
At 0 ° C., 6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropylphenyl) -4- (piperazine-1-yl) quinazoline-2 (1H) -one and DIPEA Acryloyl chloride (0.079 mL, 0.98 mmol) was added to (0.85 mL, 4.9 mmol) ice-cooled DCM solution (10 mL) and the resulting mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was then diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO ₃ solution (75 mL, 3 times). The organic layer was dried over Na ₂ SO ₄ , decanted and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, EtOAc-EtOH (3: 1) 0-100% Hertz) and 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluoro-). 6-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one was obtained: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (d, J = 1.2 Hz) , 1H) 7.41-7.54 (m, 2H) 7.29-7.37 (m, 2H) 7.14 (dt, J = 7.8, 1.7 Hz, 1H) 6.70- 6.79 (m, 2H) 6.58-6.68 (m, 1H) 6.50 (d, J = 7.4 Hz, 1H) 6.39 (dd, J = 16.8, 1.8) Hz, 1H) 5.75-5.84 (m, 1H) 3.79-4.06 (m, 8H) 3.75 (s, 2H) 3.66 (s, 1H) 2.69 (tt, J = 13.4, 6.8 Hz, 1H) 1.20-1.24 (m, 3H) 1.07 (dd, J = 6.8, 3.9 Hz, 3H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ-113.05 (s, 1F) -113.55 (s, 1F). m / z (ESI, + ve) 561.2 (M + H) ⁺ .

Step 9: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2- (2-propanil) phenyl) -4- (4- (2-propenoyl) -1-piperazinyl) -2 (1H) -Quinazolinone.
BBr ₃ (1M, DCE solution, 3.3 mL, 3.3 mmol), 4- (4-acryloylpiperazin-1-yl) -6-chloro-7- (2-fluoro-6-methoxyphenyl) -1- After adding to an ice-cooled DCE solution (1.7 mL) of (2-isopropylphenyl) quinazoline-2 (1H) -one (0.372 g, 0.663 mmol), the resulting mixture was stirred at 0 ° C. for 20 minutes. The temperature was raised to room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of NaHCO ₃ was added to the reaction mixture, followed by EtOAc (150 mL). The organic layer was separated and washed with saturated aqueous NaHCO ₃ solution (100 mL, 3 times). Then, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica, EtOAc-EtOH (3: 1) 0-100% Hertz) and 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2- (2). - propanil) phenyl) -4- (4- (2-propenoyl) -1-piperazinyl) -2 (IH) - quinazolinone was ^{obtained: 1 H NMR (400 MHz,} DMSO-d 6) δ 10.06 (br . D., J = 15.1 Hz, 1H) 8.03 (d, J = 1.2 Hz, 1H) 7.51-7.56 (m, 1H) 7.45 (t, J = 7. 6 Hz, 1H) 7.33 (tdd, J = 7.5, 7.5, 3.8, 1.4 Hz, 1H) 7.14-7.25 (m, 2H) 6.84 (dd, dd, J = 16.8, 10.4 Hz, 1H) 6.62-6.74 (m, 2H) 6.14-6.26 (m, 2H) 5.71-5.78 (m, 1H) 3 .71-3.99 (m, 8H) 2.52-2.59 (m, 1H) 1.02-1.12 (m, 6H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-113.6 (s, 1F) -114.8 (s, 1F). m / z (ESI, + ve) 547.1 (M + H) ⁺ .

ステップ１：７−ブロモ−４，６−ジクロロ−１−（２−イソプロピルフェニル）キナゾリン−２（１Ｈ）−オン。
７−ブロモ−６−クロロ−１−（２−イソプロピルフェニル）キナゾリン−２，４（１Ｈ，３Ｈ）−ジオン（中間体Ｆ、４７０ｍｇ、１．１９４ｍｍｏｌ）とＤＩＰＥＡ（０．６２３ｍＬ、３．５８ｍｍｏｌ）との混合アセトニトリル溶液（１１．４ｍＬ）にオキシ塩化リン（０．９１５ｍＬ、５．９７ｍｍｏｌ）を加えた。得られた混合物を８０℃で２時間加熱し、その後、室温に冷却して減圧濃縮し、７−ブロモ−４，６−ジクロロ−１−（２−イソプロピルフェニル）キナゾリン−２（１Ｈ）−オンが得られた：ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４１３．０ （Ｍ＋Ｈ）^＋。 Method 9
Example 9-1: 6-chloro-7- (2,3-dichloro-5-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1 -(2- (2-Propanil) phenyl) -2 (1H) -quinazolinone

Step 1: 7-Bromo-4,6-dichloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -on.
7-Bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione (intermediate F, 470 mg, 1.194 mmol) and DIPEA (0.623 mL, 3.58 mmol) Phosphorus oxychloride (0.915 mL, 5.97 mmol) was added to the mixed acetonitrile solution (11.4 mL). The resulting mixture was heated at 80 ° C. for 2 hours, then cooled to room temperature and concentrated under reduced pressure to 7-bromo-4,6-dichloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one. Was obtained: m / z (ESI, + ve) 413.0 (M + H) ⁺ .

Step 2: (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one.
7-Bromo-4,6-dichloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one (492 mg, 1.19 mmol), (S) -4-N-boc-2-methylpiperazine (478 mg) A DMF solution (2.3 mL) of a mixture of 2.39 mmol) and DIPEA (0.623 mL, 3.58 mmol) was stirred at room temperature for 10 minutes. Then ice water (10 mL) was added and the resulting mixture was stirred for 15 minutes. The precipitated solid is collected by filtration, washed with water and dried under vacuum to 4- (7-bromo-6-chloro-1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-. 4-Il) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl was obtained: m / z (ESI, + ve) 577.1 (M + H) ⁺ .

TFA (2.0 mL, 26.8 mmol), 4- (7-bromo-6-chloro-1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) -3-yl Methylpiperazine-1-carboxylic acid (S) -tert-butyl (297 mg, 0.516 mmol) was added to a DCM solution (2.0 mL) and the resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was concentrated under reduced pressure and (S) -7-bromo-6-chloro-1- (2-isopropylphenyl) -4- (2-methylpiperazin-1-yl) quinazoline-2 (1H) -one. Obtained: m / z (ESI, + ve) 477.0 (M + H) ⁺ .

Acryloyl chloride (0.258 M DCM solution, 4.0 mL, 1.031 mmol), (S) -7-bromo-6-chloro-1- (2-isopropylphenyl) -4- (2-methylpiperazin-1-) Il) Quinazoline-2 (1H) -one and DIPEA (0.269 mL, 1.547 mmol) were added to an ice-cooled mixed DCM solution (2.0 mL), and the resulting mixture was stirred at 0 ° C. for 20 minutes. After concentration under reduced pressure, the residue was purified by chromatography (silica, EtOAc-EtOH (3: 1) 0-100% hertz) and (S) -4- (4-acryloyl-2-methylpiperazin-1-yl). ) -7-Bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one was obtained: ¹ H NMR (400 MHz, DMSO-d6) δ 7.91-8.08 (M, 1H), 7.49-7.67 (m, 2H), 7.41 (br d, J = 5.8 Hz, 1H), 7.21 (br s, 1H), 6.76- 6.98 (m, 1H), 6.52-6.67 (m, 1H), 6.09-6.29 (m, 1H), 5.75 (br s, 1H), 4.61-4 .96 (m, 1H), 4.23-4.48 (m, 1H), 3.93-4.21 (m, 2H), 3.50-3.77 (m, 1H), 3.33 -3.49 (m, 1H), 3.23-3.28 (m, 1H), 2.94-3.24 (m, 1H), 1.27 (br d, J = 9.3 Hz, 6H), 1.09 (br s, 3H). m / z (ESI, + ve) 531.1 (M + H) ⁺ .

Step 3: (S) -4- (4-Acryloyl-2-methylpiperazin-1-yl) -6-chloro-7- (2,3-dichloro-5-methoxyphenyl) -1- (2-isopropylphenyl) ) Quinazoline-2 (1H) -on.
(S) -4- (4-Acryloyl-2-methylpiperazin-1-yl) -7-bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one (120 mg, 0. 226 mmol), 2- (2,3-dichloro-5-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (82 mg, 0.272 mmol), Na ₂ CO ₃ (96 mg) , 0.906 mmol), and a mixture of 1,4-dioxane solution (1.6 mL) and water (0.4 mL) in which a mixture of Pd (PPh ₃ ) ₄ (26.2 mg, 0.023 mmol) was dissolved. Was heated at 90 ° C. for 17 hours. The reaction mixture was then concentrated under reduced pressure and purified by chromatography (silica gel, EtOAc-EtOH (3: 1) 0-100% heptan) and (S) -4- (4-acryloyl-2-methylpiperazin-1). -Il) -6-chloro-7- (2,3-dichloro-5-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one was obtained: m / z (ESI, + ve) ) 627.0 (M + H) ⁺ .

Step 4: 6-Chloro-7- (2,3-dichloro-5-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2) -(2-Propanil) phenyl) -2 (1H) -quinazolinone.
BBr ₃ (1M hexane solution, 0.32 mL, 0.320 mmol), (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-chloro-7- (2,3-dichloro) Obtained by adding to an ice-cooled mixture of -5-methoxyphenyl) -1- (2-isopropylphenyl) quinazoline-2 (1H) -one (40 mg, 0.064 mmol) and DCE (1.0 mL). The mixture was stirred at 0 ° C. for 30 minutes. A ₃ aqueous saturated NaHCO solution (2.0 mL) was added and the resulting mixture was extracted with DCM / MeOH (2: 1) (5 mL). The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, DCM containing 0-10% MeOH) and 6-chloro-7- (2,3-dichloro-5-hydroxyphenyl) -4-((2S) -2-methyl-4-). (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanyl) phenyl) -2 (IH) - quinazolinone was ^{obtained: 1 H NMR (400 MHz,} DMSO-d6) δ 10.42 (Br d, J = 17.0 Hz, 1H), 7.86-8.11 (m, 1H), 7.50-7.63 (m, 1H), 7.47 (br t, J = 6) .0 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.15-7.26 (m, 1H), 7.05 (d, J = 2.3 Hz, 1H) ), 6.78-6.96 (m, 1H), 6.44-6.58 (m, 1H), 6.11-6.29 (m, 2H), 5.71-5.82 (m) , 1H) 4.68-4.98 (m, 1H) 3.96-4.52 (m, 3H), 3.52-3.85 (m, 2H) 3.34-3.51 (M, 1H), 2.95-3.26 (m, 1H), 1.27-1.41 (m, 3H), 0.95-1.13 (m, 6H). m / z (ESI, + ve) 611.0 (M + H) ⁺ .

ステップ１：６，７−ジクロロ−２，３−ジヒドロフタラジン−１，４−ジオン（中間体Ｇ）。
ヒドラジン（０．２３２ｍＬ、１０．１ｍｍｏｌ）を、５，６−ジクロロイソベンゾフラン−１，３−ジオン（２．００ｇ、９．２２ｍｍｏｌ、ＴＣＩ Ａｍｅｒｉｃａ、Ｐｏｒｔｌａｎｄ、ＯＲ、ＵＳＡ）とエタノール（３０ｍＬ）との混合物に加え、得られた混合物を還流で２時間加熱してから室温に冷却した。生じた析出物をろ過によって回収し、水で洗浄し、６，７−ジクロロ−２，３−ジヒドロフタラジン−１，４−ジオンが得られた：ｍ／ｚ （ＥＳＩ、＋ｖｅ） ２３１．１ （Ｍ＋Ｈ）^＋。 Method 10
Examples 10-1: 1- (4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (2-methylphenyl) -1-phthalazinyl) -1-piperazinyl) -2- Propene-1-on.

Step 1: 6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G).
Hydrazine (0.232 mL, 10.1 mmol) with 5,6-dichloroisobenzofuran-1,3-dione (2.00 g, 9.22 mmol, TCI America, Portland, OR, USA) and ethanol (30 mL). In addition to the mixture, the resulting mixture was heated at reflux for 2 hours and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with water to give 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione: m / z (ESI, + ve) 231.1. (M + H) ⁺ .

Step 2: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -2,3-dihydrophthalazine-1,4-dione.
6,7-Dichloro-2,3-dihydrophthalazine-1,4-dione (intermediate G, 3.80 g, 16.45 mmol), 2-fluoro-6-hydroxyphenylboronic acid (10.26 g, 65. DME solution of a mixture of 8 mmol, Combi-blocks Inc., San Diego, CA, USA), SPhos Pd G3 (1.423 g, 1.645 mmol), and 2M Na ₂ CO ₃ aqueous solution (32.9 mL, 65.8 mmol). (60 mL) was stirred at 80 ° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (200 mL) and EtOAc (300 mL). The aqueous layer was separated, acidified with 5N HCl and extracted with EtOAc (300 mL). The combined organic layers were washed with brine (200 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was suspended in DCM (50 mL) and collected by filtration to give 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -2,3-dihydrophthalazine-1,4-dione. : M / z (ESI, + ve) 307.0 (M + H) ⁺ .

Step 3: 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-2,3-dihydrophthalazine-1,4-dione.
tert-Butyl (chloro) diphenylsilane (2.67 mL, 10.25 mmol), 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -2,3-dihydrophthalazine-1,4-dione ( Add to ice-cooled mixed acetonitrile solution (40 mL) of 2.62 g, 8.54 mmol) and TEA (4.75 mL, 34.2 mmol), stir the resulting mixture at 0 ° C. for 15 minutes, then raise to room temperature. It was warmed and stirred for 1.5 hours. Further tert-butyl (chloro) diphenylsilane (2.67 mL, 10.25 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (300 mL), acidified with 5N HCl and extracted with EtOAc (300 mL). The organic layer was separated, washed successively with brine (250 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was taken on DCM (200 mL), TFA (20 mL) was added and the resulting mixture was stirred at room temperature for 45 minutes. The reaction mixture was then diluted with saturated aqueous NaHCO ₃ solution (200 mL) and extracted with DCM (250 mL, twice). The combined organic extracts were dried over sulfonyl ₄ , filtered and concentrated under reduced pressure to 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-2,3-dihydro. Phenylazine-1,4-dione was obtained: m / z (ESI, + ve) 545.2 (M + H) ⁺ .

Step 4: 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -1,4,7-trichlorophthalazine.
Pyridine (1.45 mL, 17.1 mmol), 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-2,3-dihydrophthalazine-1,4- It was added to a mixture of dione (4.66 g, 8.55 mmol) and phosphorus oxychloride (6.39 mL, 68.4 mmol) and the resulting mixture was heated at 100 ° C. for 1.5 hours. The reaction mixture was then cooled to room temperature and slowly poured into stirred water (300 mL) while maintaining an internal temperature below 10 ° C. After stirring for 15 minutes, the resulting mixture was extracted with EtOAc (400 mL) and the organic extracts were sequentially washed with brine (250 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing EtOAc to 25%) to give 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -1,4,7-trichlorophthalazine. Obtained: m / z (ESI, + ve) 581.1 (M + H) ⁺ .

Step 5: 4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl ( Intermediate H).
1-Boc-piperazine (5.00 g, 26.9 mmol), 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -1,4,7-trichlorophthalazine (5. A mixture of 21 g (8.95 mmol) and triethylamine (3.77 mL, 26.9 mmol) was added to a mixed DCM solution (35 mL) and the resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was then partitioned between DCM (300 mL) and saturated aqueous NaHCO ₃ solution (200 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0 to 50% EtOAc) and 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine). -1-Il) piperazin-1-carboxylate tert-butyl and 4-(7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,6-dichlorophthalazine-1- A mixture of tert-butyl piperazin-1-carboxylate was obtained. Individual positional isomers were isolated by chiral SFC purification (OJ-H column (30 x 250 mm, 5 μm), 15% in supercritical CO ₂ (20 mM NH _3- containing MeOH)) and 4- (6- (2- (2- (2- (20 mM)). the (tert- butyldiphenylsilyl) oxy) -6-fluoro-phenyl) -4,7-dichloro-phthalazine-1-yl) piperazine-1-carboxylic acid tert- butyl was obtained as the second eluting ^isomer: 1 H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H) 8.17 (s, 1H) 7.56-7.61 (m, 4H) 7.40-7.46 (m, 2H) 7. 31-7.37 (m, 4H) 6.99-7.07 (m, 1H) 6.77 (t, J = 8.61 Hz, 1H) 6.42 (d, J = 8.22 Hz, 1H) 3.72-3.77 (m, 4H) 3.53-3.59 (m, 4H) 1.51 (s, 9H) 0.66 (s, 9H). m / z (ESI, + ve) 731.2 (M + H) ⁺ .

Step 6: 6- (2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichloro-1- (piperazine-1-yl) phthalazine.
Trifluoroacetic acid (2 mL, 26.8 mmol) was stirred with 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl). ) Tert-Butyl piperazin-1-carboxylate (intermediate H, 1.21 g, 1.654 mmol) was added to a DCM solution (10 mL) and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with saturated aqueous NaHCO ₃ solution (75 mL) and extracted with DCM (100 mL, twice). The combined organic extracts were dried on sulfonyl ₄ , filtered and concentrated under reduced pressure to 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichloro-1-( Piperazine-1-yl) Phthalazine was obtained: m / z (ESI, + ve) 631.3 (M + H) ⁺ .

Step 7: 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazine-1-yl) propa -2-en-1-on.
Acryloyl chloride (0.148 mL, 1.81 mmol), 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichloro-1- (piperazine-1-yl) A mixture of phthalazine (1.04 g, 1.647 mmol) and triethylamine (0.694 mL, 4.94 mmol) was added to a mixed DCM solution (10 mL), and the resulting mixture was stirred at room temperature for 45 minutes. A ₃ aqueous saturated NaHCO solution (75 mL) was added and the resulting mixture was extracted with DCM (100 mL, 3 times). The combined organic extracts were dried over MgSO _4, filtered and concentrated in vacuo, 1- (4- (6- (2 - ((tert- butyldiphenylsilyl) oxy) -6-fluoro-phenyl) 4,7 -Dichlorophthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one was obtained: m / z (ESI, + ve) 685.1 (M + H) ⁺ .

Step 8: 1- (4- (4,7-dichloro-6- (2-fluoro-6-hydroxyphenyl) phthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one (intermediate) Body I).
TBAF (1M THF solution, 3.3 mL, 3.30 mmol), 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthal Radin-1-yl) piperazine-1-yl) propa-2-ene-1-one (1.13 g, 1.648 mmol) was added to a THF solution (10 mL) and the resulting mixture was stirred at room temperature for 15 minutes. .. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, Hertz containing 0-100% EtOAc) 1- (4- (4,7-dichloro-6- (2-fluoro-6-hydroxyphenyl)). ) Phthalazine-1-yl) Piperazine-1-yl) Propa-2-en-1-one was obtained: ¹ H NMR (400 MHz, DMSO-d6) δ 10.26 (br s, 1H) 8. 31 (s, 1H) 8.14 (s, 1H) 7.31-7.40 (m, 1H) 6.78-6.92 (m, 3H) 6.17 (dd, J = 16.63, 2.35 Hz, 1H) 5.74 (dd, J = 10.37, 2.35 Hz, 1H) 3.79-3.92 (m, 4H) 3.46-3.55 (m, 4H) .. m / z (ESI, + ve) 447.0 (M + H) ⁺ .

Step 9: 1- (4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (o-tolyl) phthalazine-1-yl) piperazine-1-yl) propa-2-ene -1-On.
1- (4- (4,7-dichloro-6- (2-fluoro-6-hydroxyphenyl) phthalazine-1-yl) piperazin-1-yl) propa-2-ene-1-one (intermediate I, 25 mg, 0.056 mmol), 2-trilbolonic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan UT, USA), Pd (PPh ₃ ) ₄ (6.46 mg, 5.59 μmol, Strem Chemicals Inc.). , NewburyPort, MA, USA), and a 1,4-dioxane solution (0.3 mL) of a mixture of 2M Na ₂ CO ₃ aqueous solution (0.084 mL, 0.168 mmol) was stirred at 40 ° C. for 18 hours. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated, washed successively with brine (15 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing EtOAc 0 to 100%) and 1- (4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (o-tolyl) phthalazine-. 1-Il) piperazine-1-yl) propa-2-ene-1-one was given: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.15 (br s, 1H) 8.33 (s) , 1H) 7.36-7.45 (m, 2H) 7.24-7.36 (m, 4H) 6.90 (dd, J = 16.63, 10.37 Hz, 1H) 6.70- 6.80 (m, 2H) 6.18 (dd, J = 16.73, 2.25 Hz, 1H) 5.75 (dd, J = 10.56, 2.15 Hz, 1H) 3.83- 3.97 (m, 4H) 3.47-3.62 (m, 4H) 1.98-2.06 (m, 3H). m / z (ESI, + ve) 503.1 (M + H) ⁺ .

ステップ１：４−（１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール−１−イル）−７−ブロモ−６−クロロ−１−（２−イソプロピルフェニル）キナゾリン−２（１Ｈ）−オン。
オキシ塩化リン（１．２０４ｍＬ、７．８５ｍｍｏｌ）を、７−ブロモ−６−クロロ−１−（２−イソプロピルフェニル）キナゾリン−２，４（１Ｈ，３Ｈ）−ジオン（中間体Ｆ、５１５ｍｇ、１．３０８ｍｍｏｌ）、トリエチルアミン（３．３１ｍＬ、２３．５５ｍｍｏｌ）、及び１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール（２．０１ｇ、１６．８７ｍｍｏｌ）の混合物の撹拌したアセトニトリル溶液（１５ｍＬ）に加えた。反応混合物を８０℃に加熱し、１時間撹拌した。反応混合物を室温に冷却し、ろ過した。その後、ろ液を約１０℃で急速に撹拌された水（１５０ｍＬ）にゆっくりと注いだ。水性懸濁液を１５分間撹拌してから、ＥｔＯＡｃ（１５０ｍＬ）で２回抽出した。有機層を合わせて食塩水（１５０ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮し、粗４−（１Ｈ−ベンゾ［ｄ］［１，２，３］トリアゾール−１−イル）−７−ブロモ−６−クロロ−１−（２−イソプロピルフェニル）キナゾリン−２（１Ｈ）−オンが得られた。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ ４９４．０。 Method 11
Examples 11-1: 6-chloro-7- (5-methyl-1H-indazole-4-yl) -1- (2- (2-propanil) phenyl) -4- (4- (2-propenoyl)- 1-Piperadinyl) -2 (1H) -quinazolinone

Step 1: 4- (1H-benzo [d] [1,2,3] triazole-1-yl) -7-bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one ..
Phosphoryl oxychloride (1.204 mL, 7.85 mmol), 7-bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2,4 (1H, 3H) -dione (intermediate F, 515 mg, 1) In a stirred acetonitrile solution (15 mL) of a mixture of .308 mmol), triethylamine (3.31 mL, 23.55 mmol), and 1H-benzo [d] [1,2,3] triazole (2.01 g, 16.87 mmol). added. The reaction mixture was heated to 80 ° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was then slowly poured into rapidly stirred water (150 mL) at about 10 ° C. The aqueous suspension was stirred for 15 minutes and then extracted twice with EtOAc (150 mL). The organic layers are combined, washed with saline (150 mL), dried over phenyl ₄ , filtered and concentrated under reduced pressure, crude 4- (1H-benzo [d] [1,2,3] triazole-1-yl). -7-Bromo-6-chloro-1- (2-isopropylphenyl) quinazoline-2 (1H) -one was obtained. m / z (ESI) M + H 494.0.

Step 2: tert-butyl 4- (7-bromo-6-chloro-1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazine-1-carboxylate.
Tert-Butyl piperazine-1-carboxylate (268 mg, 1.438 mmol) in crude 4- (1H-benzo [d] [1,2,3] triazole-1-yl) -7-bromo-6-chloro- It was added to a stirred mixed dimethyl sulfoxide solution (6 mL) of 1- (2-isopropylphenyl) quinazoline-2 (1H) -one (647 mg, 1.308 mmol) and triethylamine (3.68 mL, 26.2 mmol). The reaction mixture was stirred at 80 ° C. for 30 minutes. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (75 mL). The organic layer was separated, washed with brine (75 mL), dried over plate ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing EtOAc 0 to 100%) and 4- (7-bromo-6-chloro-1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4. -Il) Piperazine-1-carboxylate tert-butyl was obtained. ¹ H NMR (400 MHz, chloroform-d) δ 7.79 (1 H, s) 7.49-7.59 (2 H, m) 7.36-7.42 (1 H, m) 7.11 (1 H, d, J = 7.63 Hz) 6.80 (1 H, s) 3.79-3.92 (4 H, m) 3.62-3.73 (4 H, m) 2. 60 (1 H, spt, J = 6.80 Hz) 1.49-1.54 (9 H, m) 1.22 (3 H, d, J = 6.85 Hz) 1.08 (3 H, d, J = 6.85 Hz). m / z (ESI) M + H: 561.0.

Step 3: 4- (6-chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H-indazole-4-yl) -2-oxo-1,2-dihydroquinazoline-4-yl) Piperazine-1-carboxylate tert-butyl.
4- (7-Bromo-6-chloro-1- (2-isopropylphenyl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazin-1-carboxylic acid tert in a sealed vial under an argon atmosphere -Butyl (115 mg, 0.205 mmol), 4-borono-5-methyl-1h-indazole (0.144 mL, 0.819 mmol, Ark Pharm Inc., Arlington Heights, IL, USA), SPhos Pd G3 (0.016 mL) , 0.020 mmol), and sodium carbonate (2M aqueous solution, 0.409 mL, 0.819 mmol) was mixed with 1,2-dimethoxyethane (1 mL). The reaction mixture was stirred at 100 ° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, (Heptane containing (EtOAc / EtOH 3: 1) 0-50%) and 4- (6-chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H). -Indazole-4-yl) -2-oxo-1,2-dihydroquinazoline-4-yl) piperazine-1-carboxylate tert-butyl was obtained. m / z (ESI) M + H: 613.2.

Step 4: 6-Chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H-indazole-4-yl) -4- (piperazine-1-yl) quinazoline-2 (1H) -one.
Trifluoroacetic acid (0.5 mL, 6.71 mmol), 4- (6-chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H-indazole-4-yl) -2-oxo- It was added to a stirred mixed dichloromethane solution (1 mL) of tert-butyl 1,2-dihydroquinazoline-4-yl) piperazine-1-carboxylate (78 mg, 0.127 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and crude 6-chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H-indazole-4-yl) -4- (piperazine-1-yl) quinazoline-2 ( 1H) -On was obtained. m / z (ESI) M + H: 513.2.

Step 5: 6-Chloro-7- (5-methyl-1H-indazole-4-yl) -1- (2- (2-propanil) phenyl) -4- (4- (2-propenoyl) -1-piperazinyl) ) -2 (1H) -quinazolinone.
Acryloyl chloride (10.33 μl, 0.127 mmol), 6-chloro-1- (2-isopropylphenyl) -7- (5-methyl-1H-indazole-4-yl) -4- (piperazine-1-yl) ) Quinazoline-2 (1H) -one (65 mg, 0.127 mmol) and triethylamine (0.178 mL, 1.267 mmol) were added to a stirred mixed dichloromethane solution (2 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 20 minutes. Further acryloyl chloride (5.17 μl, 0.064 mmol) was added and the reaction mixture was stirred at 0 ° C. for an additional 20 minutes. The reaction mixture was diluted with DCM (25 mL) and the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, (EtOAc / EtOH 3: 1) 0-80% heptane) to give an impure product. The impure product was further purified by chromatography (silica gel, heptane containing 0-100% acetone) to give the separated diastereomers. The first diastereomer to be eluted is 6-chloro-7- (5-methyl-1H-indazole-4-yl) -1- (2- (2-propanil) phenyl) -4- (4- (2). It was −propenoyl) -1-piperazinyl) -2 (1H) -quinazolinone (Example 11-1-1). ^{1 1} H NMR (400 MHz, chloroform-d) δ 10.28 (1 H, br s) 7.94 (1 H, s) 7.35-7.49 (4 H, m) 7.25-7. 31 (2 H, m) 7.11 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J = 16.79, 10.57 Hz) 6.54 (1 H, m) s) 6.41 (1 H, dd, J = 16.79, 1.87 Hz) 5.81 (1 H, dd, J = 10.57, 1.66 Hz) 3.83-4.07 ( 8 H, m) 2.74 (1 H, spt, J = 6.84 Hz) 2.13 (3 H, s) 1.23 (3 H, d, J = 6.84 Hz) 1.04 ( 3 H, d, J = 6.84 Hz). m / z (ESI) M + H: 567.2. The second diastereomer to be eluted was further purified by column chromatography (silica gel, (Heptane containing (EtOAc / EtOH 3: 1) 0 to 80%) and 6-chloro-7- (5-methyl-1H-indazole-). 4-Il) -1- (2- (2-propanol) phenyl) -4- (4- (2-propenoyl) -1-piperazinyl) -2 (1H) -quinazolinone was obtained (Example 11-1). -2). ^{1 1} H NMR (400 MHz, chloroform-d) δ 10.37 (1 H, br s) 7.94 (1 H, s) 7.34-7.50 (4 H, m) 7.21-7. 31 (2 H, m) 7.13 (1 H, d, J = 7.67 Hz) 6.64 (1 H, dd, J = 16.90, 10.68 Hz) 6.55 (1 H, m) s) 6.41 (1 H, dd, J = 16.79, 1.66 Hz) 5.81 (1 H, dd, J = 10.47, 1.55 Hz) 3.83-4.08 ( 8 H, m) 2.70 (1 H, spt, J = 6.84 Hz) 2.13 (3 H, s) 1.22 (3 H, d, J = 6.84 Hz) 1.03 ( 3 H, d, J = 6.84 Hz). m / z (ESI) M + H: 567.2.
The above method 11, steps 1 to 5 are as follows:

ステップ１：４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−シクロプロピルフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−４，７−ジクロロフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｈ、０．０６０ｇ、０．０８２ｍｍｏｌ）を投入した２０ｍＬバイアルに、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（０．０３３ｇ、０．０４１ｍｍｏｌ）及び２−メチルテトラヒドロフラン（２．０ｍＬ）を加えた。得られた混合物を封止し、室温で１０分間撹拌してから、シクロプロピル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、０．８２０ｍＬ、０．４１０ｍｍｏｌ；Ｒｉｅｋｅ Ｍｅｔａｌｓ、Ｌｉｎｃｏｌｎ、ＮＥ、ＵＳＡ）をシリンジで加えた。反応混合物を８０℃で３時間加熱してから、室温に冷却し、ＥｔＯＡｃ（３０ｍＬ）と水（１０ｍＬ）で分配した。水層をＥｔＯＡｃ（２０ｍＬ）でもう一度抽出した。合わせた有機層をＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮した。粗生成物をカラムクロマトグラフィー（シリカゲル２４ｇ、アセトン０〜３０％含有ヘプタン）で精製し、４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−シクロプロピルフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た。^１Ｈ ＮＭＲ （クロロホルム−ｄ） δ： ８．３１−８．３８ （ｍ、１Ｈ）、８．１５−８．２３ （ｍ、１Ｈ）、７．５５−７．６４ （ｍ、４Ｈ）、７．３９−７．４７ （ｍ、２Ｈ）、７．２９−７．３８ （ｍ、４Ｈ）、６．９９−７．０９ （ｍ、１Ｈ）、６．７４−６．８５ （ｍ、１Ｈ）、６．３６−６．４７ （ｍ、１Ｈ）、３．６８−３．７９ （ｍ、４Ｈ）、３．３７−３．５１ （ｍ、４Ｈ）、２．３７−２．４８ （ｍ、１Ｈ）、１．４８−１．５４ （ｍ、９Ｈ）、１．３７−１．４５ （ｍ、１Ｈ）、１．３０−１．３３ （ｍ、１Ｈ）、１．００−１．１５ （ｍ、２Ｈ）、０．６１−０．７１ （ｍ、９Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ７３７．４。 Item 2-Individual Examples Example 12
1- (4- (7-Chloro-4-cyclopropyl-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropylphthalazine-1-yl) piperazine-1-carboxylic acid tert -Butyl.
4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) tert-butyl piperazine-1-carboxylate (intermediate H) , 0.060 g, 0.082 mmol) in a 20 mL vial containing [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (0.033 g, 0.041 mmol) and 2-methyl. Tetrahydrofuran (2.0 mL) was added. The resulting mixture is sealed and stirred at room temperature for 10 minutes before adding cyclopropyl zinc bromide (0.5 M THF solution, 0.820 mL, 0.410 mmol; Rieke Metals, Lincoln, NE, USA) with a syringe. It was. The reaction mixture was heated at 80 ° C. for 3 hours, then cooled to room temperature and partitioned between EtOAc (30 mL) and water (10 mL). The aqueous layer was extracted again with EtOAc (20 mL). The combined organic layers were dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 24 g, heptan containing 0 to 30% acetone) and 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-. Chromato-4-cyclopropylphthalazine-1-yl) tert-butyl piperazin-1-carboxylate was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.31-8.38 (m, 1H), 8.15-8.23 (m, 1H), 7.55-7.64 (m, 4H), 7 .39-7.47 (m, 2H), 7.29-7.38 (m, 4H), 6.99-7.09 (m, 1H), 6.74-6.85 (m, 1H) , 6.36-6.47 (m, 1H), 3.68-3.79 (m, 4H), 3.37-1.51 (m, 4H), 2.37-2.48 (m, 1H), 1.48-1.54 (m, 9H), 1.37-1.45 (m, 1H), 1.30-1.33 (m, 1H), 1.00-1.15 ( m, 2H), 0.61-0.71 (m, 9H). m / z (ESI) M + H: 737.4.

Step 2: 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropyl-1- (piperazine-1-yl) phthalazine.
Trifluoroacetic acid (0.316 mL, 4.10 mmol), 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropylphthalazine- 1-Il) Piperazine was added to a solution of tert-butyl carboxylate in DCM (0.7 mL). The resulting mixture was sealed and stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (10 mL) and made basic using saturated aqueous NaHCO ₃ solution (5 mL). The aqueous layer was extracted again with DCM (10 mL). The combined organic layers were dried on sulfonyl ₄ , filtered and concentrated under reduced pressure to 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropyl-1. -(Piperazine-1-yl) phthalazine was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.30-8.36 (m, 1H), 8.18-8.24 (m, 1H), 7.55-7.64 (m, 4H), 7 .40-7.46 (m, 2H), 7.33 (q, J = 7.1 Hz, 4H), 6.97-7.09 (m, 1H), 6.74-6.83 (m) , 1H), 6.36-6.46 (m, 1H), 3.45-3.55 (m, 4H), 3.16-3.26 (m, 4H), 2.35-2.49 (M, 1H), 1.37-1.46 (m, 1H), 1.30-1.33 (m, 1H), 1.06-1.12 (m, 2H), 0.61-0 .70 (m, 9H). m / z (ESI) M + H: 637.2.

Step 3: 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropylphthalazine-1-yl) piperazine-1- Il) Propyl-2-en-1-on.
6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropyl-1- (piperazine-1-yl) phthalazine (0.023 g, 0.036 mmol) Triethylamine (16 μl, 0.114 mmol) and dichloromethane (1.0 mL) were added to the 20 mL vial containing the above. The resulting mixture was sealed, stirred at room temperature for 10 minutes, and then acryloyl chloride (4.0 μl, 0.049 mmol) was added via syringe. The reaction mixture was sealed and stirring was continued for 20 minutes at room temperature. The reaction was stopped with saturated aqueous NaHCO ₃ solution (3 mL) and diluted with DCM (10 mL). The aqueous layer was extracted again with DCM (5 mL). The combined organic layers were dried on sulfonyl ₄ , filtered and concentrated under reduced pressure to 1-(4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro- 4-Cyclopropylphthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.32-8.38 (m, 1H), 8.16-8.24 (m, 1H), 7.55-7.65 (m, 4H), 7 .40-7.48 (m, 2H), 7.31-7.38 (m, 4H), 6.98-7.10 (m, 1H), 6.75-6.84 (m, 1H) , 6.60-6.72 (m, 1H), 6.41-6.47 (m, 1H), 6.31-6.40 (m, 1H), 5.72-5.82 (m, 1H) 3.79-4.08 (m, 4H) 3.44-3.62 (m, 4H) 2.38-2.49 (m, 1H), 1.40-1.45 (1H) m, 1H), 1.33-1.37 (m, 1H), 1.04-1.13 (m, 2H), 0.62-0.68 (m, 9H). m / z (ESI) M + H: 691.2.

Step 4: 1- (4- (7-Chloro-4-cyclopropyl-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one.
1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopropylphthalazine-1-yl) piperazine-1-yl) propa Tetrahydrofuran (2.0 mL) was added to a 20 mL vial containing -2-en-1-one (0.022 g, 0.032 mmol), then tetrabutylammonium fluoride (1.0 M THF solution, 0.070 mL, 0). .070 mmol) was added. The vial was sealed and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (Silica 24 g, DCM containing 0-5% MeOH) and 1- (4- (7-chloro-4-cyclopropyl-6- (2-fluoro-6-hydroxyphenyl) -)-. 1-phthalazinyl) -1-piperazinyl) -2-propen-1-one was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.30-8.37 (m, 1H), 8.11-8.18 (m, 1H), 7.29-7.38 (m, 1H), 6 .96-7.18 (m, 1H), 6.88-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.72 (m, 1H) , 6.31-6.42 (m, 1H), 5.73-5.84 (m, 1H), 3.73-4.05 (m, 4H), 3.35-3.62 (m, 4H), 2.40-2.52 (m, 1H), 1.35-1.42 (m, 1H), 1.29-1.34 (m, 1H), 1.03-1.14 ( m, 2H). m / z (ESI) M + H: 453.2.

ステップ１：４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−（フェニルアミノ）フタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−４，７−ジクロロフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（０．０６０ｇ、０．０８２ｍｍｏｌ）を投入した２０ｍＬバイアルにジメチルスルホキシド（２．０ｍＬ）を加え、次いでアニリン（０．０７５ｍＬ、０．８２０ｍｍｏｌ）を加えた。バイアルを封止し、８０℃で３時間還流させた。反応物を室温に冷却し、ＥｔＯＡｃ（３０ｍＬ）と水（１０ｍＬ）で分配した。有機層を分離し、水で洗浄した（１０ｍＬ、２回）。有機層をＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮した。粗生成物をカラムクロマトグラフィー（シリカ４０ｇ、ＥｔＯＡｃ０〜３０％含有ヘプタン）で精製し、４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−（フェニルアミノ）フタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た。^１Ｈ ＮＭＲ （クロロホルム−ｄ） δ： ８．１７−８．２５ （ｍ、１Ｈ）、７．７６−７．８１ （ｍ、１Ｈ）、７．６０−７．６９ （ｍ、５Ｈ）、７．５０−７．５５ （ｍ、２Ｈ）、７．４０−７．４６ （ｍ、２Ｈ）、７．３１−７．３７ （ｍ、５Ｈ）、７．０６−７．１１ （ｍ、２Ｈ）、６．７６−６．８３ （ｍ、１Ｈ）、６．５７−６．６６ （ｍ、１Ｈ）、６．３９−６．５０ （ｍ、１Ｈ）、３．６６−３．８１ （ｍ、４Ｈ）、３．３２−３．４３ （ｍ、４Ｈ）、１．５１−１．５３ （ｍ、９Ｈ）、０．６９−０．７５ （ｍ、９Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ７８８．２。 Example 13
1- (4- (4-anilino-7-chloro-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4- (phenylamino) phthalazine-1-yl) piperazine-1-carboxylic acid tert-butyl.
4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl (0.060 g) Dimethyl sulfoxide (2.0 mL) was added to a 20 mL vial containing (0.082 mmol), and then aniline (0.075 mL, 0.820 mmol) was added. The vial was sealed and refluxed at 80 ° C. for 3 hours. The reaction was cooled to room temperature and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was separated and washed with water (10 mL, twice). The organic layer was dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (40 g of silica, heptane containing 0-30% EtOAc) and 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro. Tert-Butyl of -4- (phenylamino) phthalazine-1-yl) piperazine-1-carboxylate was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.17-8.25 (m, 1H), 7.76-7.81 (m, 1H), 7.60-7.69 (m, 5H), 7 .50-7.55 (m, 2H), 7.40-7.46 (m, 2H), 7.31-7.37 (m, 5H), 7.06-7.11 (m, 2H) , 6.76-6.83 (m, 1H), 6.57-6.66 (m, 1H), 6.39-6.50 (m, 1H), 3.66-3.81 (m, 4H), 3.32-3.43 (m, 4H), 1.51-1.53 (m, 9H), 0.69-0.75 (m, 9H). m / z (ESI) M + H: 788.2.

Step 2: 7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-N-phenyl-4- (piperazine-1-yl) phthalazine-1-amine.
4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4- (phenylamino) phthalazine-1-yl) as in Example 12 and Step 2. 7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-N-phenyl-4- (piperazine-1-yl) by reaction of tert-butyl piperazin-1-carboxylate ) Phenyl-1-amine was produced. ^{1 1} H NMR (chloroform-d) δ: 8.19-8.26 (m, 1H), 7.75-7.80 (m, 1H), 7.60-7.68 (m, 5H), 7 .49-7.55 (m, 2H), 7.39-7.46 (m, 3H), 7.32-7.37 (m, 5H), 7.02-7.11 (m, 2H) , 6.75-6.84 (m, 1H), 6.59-6.67 (m, 1H), 6.43-6.53 (m, 1H), 3.35-3.47 (m, 4H), 3.16-3.27 (m, 4H), 0.70-0.76 (m, 9H). m / z (ESI) M + H: 688.2.

Step 3: 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4- (phenylamino) phthalazine-1-yl) piperazine-1 -Il) Propa-2-ene-1-on.
7- (2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-N-phenyl-4- (piperazine-1-yl) phthalazine-as in Example 12 and Step 3. 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4- (phenylamino) phthalazine-1-yl) by reaction of 1-amine) Piperazine-1-yl) propa-2-ene-1-one was produced. ^{1 1} H NMR (chloroform-d) δ: 8.16-8.24 (m, 1H), 7.77-7.84 (m, 1H), 7.62-7.67 (m, 4H), 7 .52-7.55 (m, 1H), 7.41-7.46 (m, 3H), 7.32-7.38 (m, 6H), 7.02-7.11 (m, 2H) , 6.77-6.84 (m, 1H), 6.65-6.71 (m, 1H), 6.46-6.51 (m, 1H), 6.30-6.39 (m, 2H), 5.73-5.81 (m, 1H), 3.86-4.05 (m, 4H), 3.37-1.53 (m, 4H), 0.69-0.75 ( m, 9H). m / z (ESI) M + H: 742.3.

Step 4: 1- (4- (4-anilino-7-chloro-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one.
1-(4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4- (phenylamino) phthalazine-1), as in Example 12 and Step 4. -Il) Piperazine-1-yl) propa-2-ene-1-one reaction to 1- (4- (4-anilino-7-chloro-6- (2-fluoro-6-hydroxyphenyl) -1-) Phthalazine) -1-piperazinyl) -2-propen-1-one was produced. ^{1 1} H NMR (chloroform-d) δ: 7.96-8.09 (m, 2H), 7.46-7.57 (m, 2H), 7.37-7.44 (m, 1H), 7 .29-7.33 (m, 1H), 7.20-7.26 (m, 1H), 6.96-7.07 (m, 1H), 6.81-6.87 (m, 1H) , 6.70-6.77 (m, 1H), 6.54-6.67 (m, 1H), 6.29-6.41 (m, 1H), 5.68-5.82 (m, 1H), 3.74-3.96 (m, 4H), 3.12-3.43 (m, 4H). m / z (ESI) M + H: 504.2.

ステップ１：４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−シクロペンチルフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
実施例１２、ステップ１と同様、４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−４，７−ジクロロフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｈ）及びシクロペンチル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、Ｒｉｅｋｅ Ｍｅｔａｌｓ、Ｌｉｎｃｏｌｎ、ＮＥ）の反応により４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−７−クロロ−４−シクロペンチルフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルが生成した。^１Ｈ ＮＭＲ （クロロホルム−ｄ） δ： ８．１８−８．２２ （ｍ、１Ｈ）、８．１２−８．１６ （ｍ、１Ｈ）、７．６０−７．６６ （ｍ、２Ｈ）、７．５０−７．５６ （ｍ、２Ｈ）、７．３９−７．４７ （ｍ、２Ｈ）、７．３４−７．３８ （ｍ、２Ｈ）、７．２８−７．３３ （ｍ、２Ｈ）、７．０９ （ｂｒ ｄ、Ｊ ＝ １．２ Ｈｚ、１Ｈ）、６．７５−６．８２ （ｍ、１Ｈ）、６．３７−６．４４ （ｍ、１Ｈ）、３．７２−３．７８ （ｍ、４Ｈ）、３．４４−３．５１ （ｍ、４Ｈ）、２．０３−２．２３ （ｍ、４Ｈ）、１．８７−１．９６ （ｍ、２Ｈ）、１．６７−１．７９ （ｍ、３Ｈ）、１．５１−１．５４ （ｍ、９Ｈ）、０．６２−０．６７ （ｍ、９Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ７６５．２。 Example 14
1- (4- (7-Chloro-4-cyclopentyl-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl) piperazine-1-carboxylic acid tert- Butyl.
Example 12, 4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazin-1-, as in step 1. 4- (6-(2-((tert-butyldiphenylsilyl) oxy)-by reaction of tert-butyl carboxylate (intermediate H) and cyclopentylzinc bromide (0.5 M THF solution, Rieke Metals, Linkoln, NE)) Tert-butyl 6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl) piperazin-1-carboxylate was produced. ^{1 1} H NMR (chloroform-d) δ: 8.18-8.22 (m, 1H), 8.12-8.16 (m, 1H), 7.60-7.66 (m, 2H), 7 .50-7.56 (m, 2H), 7.39-7.47 (m, 2H), 7.34-7.38 (m, 2H), 7.28-7.33 (m, 2H) , 7.09 (br d, J = 1.2 Hz, 1H), 6.75-6.82 (m, 1H), 6.37-6.44 (m, 1H), 3.72-3. 78 (m, 4H), 3.44-3.51 (m, 4H), 2.03.2.23 (m, 4H), 1.87-1.96 (m, 2H), 1.67- 1.79 (m, 3H), 1.51-1.54 (m, 9H), 0.62-0.67 (m, 9H). m / z (ESI) M + H: 765.2.

Step 2: 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentyl-1- (piperazine-1-yl) phthalazine.
4-(6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl) piperazine-as in Example 12 and Step 2. 6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentyl-1- (piperazine-1-yl) phthalazine by reaction of tert-butyl 1-carboxylic acid Was generated. ^{1 1} H NMR (chloroform-d) δ: 8.17-8.21 (m, 1H), 8.12-8.16 (m, 1H), 7.61-7.66 (m, 2H), 7 .51-7.56 (m, 2H), 7.40-7.46 (m, 2H), 7.34-7.38 (m, 2H), 7.29-7.33 (m, 2H) , 6.99-7.08 (m, 1H), 6.74-6.82 (m, 1H), 6.37-6.45 (m, 1H), 3.58-3.67 (m, 4H), 3.27-3.36 (m, 4H), 2.18-2.22 (m, 1H), 2.08-2.12 (m, 2H), 1.86-1.91 ( m, 3H), 1.69-1.77 (m, 3H), 0.59-0.67 (m, 9H). m / z (ESI) M + H: 665.2.

Step 3: 1- (4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl) piperazine-1-yl) ) Propa-2-en-1-on.
6- (2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentyl-1- (piperazin-1-yl) phthalazine, as in Example 12 and Step 3. 1-(4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl) piperazine-1-yl) by reaction Propa-2-en-1-one was produced. ^{1 1} H NMR (chloroform-d) δ: 8.18-8.25 (m, 1H), 8.13-8.17 (m, 1H), 7.61-7.67 (m, 2H), 7 .50-7.57 (m, 2H), 7.39-7.48 (m, 2H), 7.28-7.37 (m, 4H), 6.99-7.10 (m, 1H) , 6.75-6.83 (m, 1H), 6.62-6.71 (m, 1H), 6.33-6.43 (m, 2H), 5.73-5.81 (m, 1H), 3.84-4.07 (m, 4H), 3.71-3.82 (m, 1H), 3.49-3.65 (m, 4H), 1.80-1.96 ( m, 4H), 1.67-1.77 (m, 4H), 0.62-0.67 (m, 9H). m / z (ESI) M + H: 719.2.

Step 4: 1- (4- (7-Chloro-4-cyclopentyl-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one.
1-(4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -7-chloro-4-cyclopentylphthalazine-1-yl), as in Example 12 and Step 4. ) Piperazine-1-yl) Propa-2-ene-1-one reaction to 1- (4- (7-chloro-4-cyclopentyl-6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-Piperazinyl) -2-propen-1-one was produced. ^{1 1} H NMR (chloroform-d) δ: 8.10-8.22 (m, 2H), 7.29-7.38 (m, 1H), 6.86-6.93 (m, 1H), 6 .77-6.85 (m, 1H), 6.61-6.72 (m, 1H), 6.33-6.44 (m, 1H), 5.74-5.85 (m, 1H) 3.82-4.05 (m, 4H), 3.75-3.82 (m, 1H), 3.40-3.63 (m, 4H), 2.06-2.24 (m, 4H), 1.81-1.96 (m, 2H), 1.67-1.79 (m, 2H). m / z (ESI) M + H: 481.2.

ステップ１：４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−（ピペリジン−１−イル）フタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−４，７−ジクロロフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｈ、０．０６０ｇ、０．０８２ｍｍｏｌ）を投入した２０ｍＬバイアルにピペリジン（１．０ｍＬ、１０．１０ｍｍｏｌ）を加えた。バイアルを封止し、８０℃で２時間加熱した。反応物を室温に冷却し、ＥｔＯＡｃ（３０ｍＬ）と水（１０ｍＬ）で分配した。有機層を分離し、水で洗浄した（１０ｍＬ、２回）。合わせた有機層をＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮し、４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−（ピペリジン−１−イル）フタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た。^１Ｈ ＮＭＲ （クロロホルム−ｄ） δ： ８．０９−８．１４ （ｍ、１Ｈ）、７．９７−８．０３ （ｍ、１Ｈ）、７．２８−７．３５ （ｍ、１Ｈ）、６．７５−６．８８ （ｍ、２Ｈ）、３．６５−３．７６ （ｍ、４Ｈ）、３．３０−３．４４ （ｍ、８Ｈ）、１．７２−１．８１ （ｍ、４Ｈ）、１．６１−１．７１ （ｍ、３Ｈ）、１．４８−１．５３ （ｍ、９Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５４２．２。 Example 15
1- (4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (1-piperidinyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (piperidine-1-yl) phthalazine-1-yl) tert-butyl piperazin-1-carboxylate.
4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl (intermediate H) , 0.060 g, 0.082 mmol) was added to a 20 mL vial containing piperidine (1.0 mL, 10.10 mmol). The vial was sealed and heated at 80 ° C. for 2 hours. The reaction was cooled to room temperature and partitioned between EtOAc (30 mL) and water (10 mL). The organic layer was separated and washed with water (10 mL, twice). The combined organic layers were dried over MgSO _4, vacuum filtered and concentrated, 4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (piperidin-1-yl) phthalazin -1 -Il) Piperazine-1-carboxylate tert-butyl was obtained. ^{1 1} H NMR (chloroform-d) δ: 8.09-8.14 (m, 1H), 7.97-8.03 (m, 1H), 7.28-7.35 (m, 1H), 6 .75-6.88 (m, 2H), 3.65-3.76 (m, 4H), 3.30-3.44 (m, 8H), 1.72-1.81 (m, 4H) , 1.61-1.71 (m, 3H), 1.48-1.53 (m, 9H). m / z (ESI) M + H: 542.2.

Step 2: 2- (7-Chloro-1- (piperazine-1-yl) -4- (piperidine-1-yl) phthalazine-6-yl) -3-fluorophenol.
4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (piperidine-1-yl) phthalazine-1-yl) piperazin-1-carboxylic acid as in Example 12 and Step 2. The reaction of tert-butyl produced 2- (7-chloro-1- (piperazine-1-yl) -4- (piperidine-1-yl) phthalazine-6-yl) -3-fluorophenol. ^{1 1} H NMR (chloroform-d) δ: 8.09-8.13 (m, 1H), 7.95-8.03 (m, 1H), 7.28-7.38 (m, 1H), 6 .83-6.89 (m, 1H), 6.75-6.82 (m, 1H), 3.39-3.48 (m, 4H), 3.31-3.38 (m, 4H) 3.12-3.21 (m, 4H), 1.75-1.80 (m, 4H), 1.64-1.69 (m, 2H). m / z (ESI) M + H: 442.2.

Step 3: 1- (4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (1-piperidinyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1- on.
Similar to Example 12 and Step 3, by the reaction of 2- (7-chloro-1- (piperazine-1-yl) -4- (piperidine-1-yl) phthalazine-6-yl) -3-fluorophenol 1 -(4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4- (1-piperidinyl) -1-phthalazinyl) -1-piperazinyl) -2-propen-1-one was produced. .. ^{1 1} H NMR (chloroform-d) δ: 8.08-8.15 (m, 1H), 7.98-8.05 (m, 1H), 7.29-7.39 (m, 1H), 6 .86-6.94 (m, 1H), 6.76-6.85 (m, 1H), 6.59-6.70 (m, 1H), 6.30-6.43 (m, 1H) 5.72-5.84 (m, 1H), 3.77-4.05 (m, 4H), 3.40-3.56 (m, 4H), 3.32-3.38 (m, 4H), 1.73-1.85 (m, 4H), 1.64-1.70 (m, 2H). m / z (ESI) M + H: 496.2.

ステップ１：４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−フェノキシフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
乾燥した５０ｍＬ丸底フラスコにフェノール（０．１３０ｇ、１．３８１ｍｍｏｌ）及びテトラヒドロフラン（３．０ｍＬ）を投入した。混合物を０℃に冷却してから、カリウムｔ−ブトキシド（０．１５３ｇ、１．３６７ｍｍｏｌ）を加えた。混合物を０℃で１０分間撹拌してから室温に昇温させ、３０分間撹拌した。４−（６−（２−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−６−フルオロフェニル）−４，７−ジクロロフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｈ、０．１００ｇ、０．１３７ｍｍｏｌ）を加え、得られた混合物を６０℃で２時間加熱した。反応物を室温に冷却し、水で反応を停止させた。得られた混合物をＥｔＯＡｃ（３０ｍＬ）と水（１５ｍＬ）で分配した。水層をＥｔＯＡｃ（２０ｍＬ）でもう一度抽出した。合わせた有機層をＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮した。粗生成物をカラムクロマトグラフィー（シリカ４０ｇ、アセトン１０〜５０％）で精製し、４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−フェノキシフタラジン−１−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た：ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５５１．２。 Example 16
1- (4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxy-1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxyphthalazine-1-yl) piperazine-1-carboxylate tert-butyl.
Phenol (0.130 g, 1.381 mmol) and tetrahydrofuran (3.0 mL) were placed in a dry 50 mL round bottom flask. The mixture was cooled to 0 ° C. and then potassium t-butoxide (0.153 g, 1.667 mmol) was added. The mixture was stirred at 0 ° C. for 10 minutes, then warmed to room temperature and stirred for 30 minutes. 4- (6-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -4,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl (intermediate H) , 0.100 g, 0.137 mmol) was added and the resulting mixture was heated at 60 ° C. for 2 hours. The reaction was cooled to room temperature and the reaction was stopped with water. The resulting mixture was partitioned between EtOAc (30 mL) and water (15 mL). The aqueous layer was extracted again with EtOAc (20 mL). The combined organic layers were dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 40 g, acetone 10-50%) and 4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxyphthalazine-1-yl). ) Tert-Butyl piperazin-1-carboxylate was obtained: m / z (ESI) M + H: 551.2.

Step 2: 2- (7-Chloro-4-phenoxy-1- (piperazine-1-yl) phthalazine-6-yl) -3-fluorophenol.
In the same manner as in Example 12 and Step 2, by the reaction of 4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxyphthalazine-1-yl) piperazine-1-carboxylate, 2 -(7-Chloro-4-phenoxy-1- (piperazine-1-yl) phthalazine-6-yl) -3-fluorophenol was produced. ^{1 1} H NMR (chloroform-d) δ: 8.37-8.42 (m, 1H), 8.14-8.19 (m, 1H), 7.37-7.45 (m, 2H), 7 .29-7.34 (m, 1H), 7.19-7.25 (m, 2H), 6.89-6.98 (m, 1H), 6.76-6.87 (m, 4H) 3.36-3.45 (m, 4H), 3.13-3.22 (m, 4H). m / z (ESI) M + H: 451.2.

Step 3: 1- (4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxy-1-phthalazinyl) -1-piperazinyl) -2-propene-1-one.
Similar to Example 12 and Step 3, 1- (4- (7) -(7-chloro-4-phenoxy-1- (piperazine-1-yl) phthalazine-6-yl) -3-fluorophenol reaction. −Chloro-6- (2-fluoro-6-hydroxyphenyl) -4-phenoxy-1-phthalazinyl) -1-piperazinyl) -2-propen-1-one was produced. ^{1 1} H NMR (chloroform-d) δ: 8.41-8.45 (m, 1H), 8.17-8.20 (m, 1H), 7.40-7.45 (m, 2H), 7 .28-7.37 (m, 2H), 7.20-7.26 (m, 1H), 6.78-6.87 (m, 2H), 6.59-6.70 (m, 1H) , 6.31-6.41 (m, 1H), 5.97-6.06 (m, 1H), 5.74-5.81 (m, 1H), 3.76-4.03 (m, 4H), 3.38-3.53 (m, 4H). m / z (ESI) M + H: 505.2.

ステップ１：４−（５−クロロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｄ、４５９ｍｇ、１．０２ｍｍｏｌ）、（３−メトキシナフタレン−１−イル）ボロン酸（８２３ｍｇ、４．０７ｍｍｏｌ）及び炭酸セシウム（１．３３ｇ、４．０７ｍｍｏｌ）を１，４−ジオキサン（８ｍＬ）と水（２ｍＬ）の混合液に溶解させたスラリーをアルゴン流で脱気した。テトラキス（トリフェニルホスフィン）パラジウム（１１８ｍｇ、０．１０ｍｍｏｌ）を加え、混合物を再度アルゴン流で脱気した。反応混合物を密封し、１００℃で２３時間加熱した。反応物を室温に冷却し、食塩水（６０ｍＬ）で希釈し、ＥｔＯＡｃで２回抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＭｅＯＨ０〜２％含有ＤＣＭ）で精製し、４−（５−クロロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５２８．０。 Examples 17-1 and 17-2
(2E) -1- (4- (5-Chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -4- ( Dimethylamino) -2-butene-1-one (Example 17-1) and (2E) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2) , 1-Benzothiazole-3-yl) -1-piperazinyl) -4- (dimethylamino) -2-butene-1-one (Example 17-2)

Step 1: 4- (5-Chloro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl.
4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (intermediate D, 459 mg, 1.02 mmol), (3-methoxy A slurry obtained by dissolving naphthalene-1-yl) boronic acid (823 mg, 4.07 mmol) and cesium carbonate (1.33 g, 4.07 mmol) in a mixture of 1,4-dioxane (8 mL) and water (2 mL). Degassed with an argon stream. Tetrakis (triphenylphosphine) palladium (118 mg, 0.10 mmol) was added and the mixture was degassed again with an argon stream. The reaction mixture was sealed and heated at 100 ° C. for 23 hours. The reaction was cooled to room temperature, diluted with brine (60 mL) and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0-2% of MeOH) and 4- (5-chloro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl). Obtained tert-butyl piperazine-1-carboxylate. m / z (ESI) M + H: 528.0.

Step 2: 5-Chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) benzo [c] isothiazole.
DCM solution of 4- (5-chloro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (327 mg, 0.56 mmol) ( Trifluoroacetic acid (1.04 mL, 13.9 mmol) was added to 6 mL) with a syringe. The resulting yellow solution was stirred at room temperature for 4 hours and then concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0 to 25% MeOH) and 5-chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) benzo [c]. A mono-TFA salt of isothiazole was obtained. m / z (ESI) M + H: 428.0.

Step 3: (2E) -1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl)- 4- (Dimethylamino) -2-buten-1-one.
5-Chloro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) benzo [c] isothiazole (74 mg mono-TFA salt, 0.14 mmol) and trans-4-dimethyl Thionyl chloride (41 μL, 0.69 mmol) was added to a DMA solution (2 mL) of aminocrotonate (38 mg, 0.23 mmol) with a syringe. The resulting brown solution was stirred at room temperature for 2.5 hours. The reaction of the reaction mixture was stopped with water (50 mL) and extracted with DCM / MeOH (8: 1). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0-15% MeOH) and (2E) -1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl)-)-. 2,1-Benzothiazole-3-yl) -1-piperazinyl) -4- (dimethylamino) -2-buten-1-one was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.46-7.55 (m, 2H) , 7.27-7.35 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H), 6.61-6.72 (m, 2H), 3.94 (s, 3H) ), 3.80-3.93 (m, 4H), 3.62-3.68 (m, 4H), 3.07 (d, J = 4.3 Hz, 2H), 2.18 (s, 6H). m / z (ESI) M + H: 539.2.

Step 4: (2E) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl)- 4- (Dimethylamino) -2-buten-1-one.
At 0 ° C., (2E) -1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) ) -4- (Dimethylamino) -2-butene-1-one (23.5 mg, 0.044 mmol) in a 1,2-dichloroethane solution (4 mL) with boron tribromide (1.0 M hexane solution, 218 μL, 0). .22 mmol) was added dropwise with a syringe. The resulting yellow slurry was stirred for 2.75 hours at 0 ° C., then quenched with saturated aqueous NaHCO ₃ (4 mL). The mixture was extracted twice with a 4: 1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0-18% MeOH) and (2E) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl)-)-. 2,1-Benzothiazole-3-yl) -1-piperazinyl) -4- (dimethylamino) -2-buten-1-one was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.40 -7.46 (m, 1H), 7.19-7.30 (m, 3H), 7.07 (d, J = 2.4 Hz, 1H), 6.62-6.71 (m, 2H) ), 3.80-3.93 (m, 4H), 3.62-3.69 (m, 4H), 3.07 (d, J = 4.1 Hz, 2H), 2.17 (s, 6H). m / z (ESI) M + H: 525.0.

ステップ１：１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシ−１−ナフタレニル）−２，１−ベンゾチアゾール−３−イル）−１−ピペラジニル）−２−（ヒドロキシメチル）−２−プロペン−１−オン。
バイアルに、１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン（中間体Ｏ、２９ｍｇ、０．０６ｍｍｏｌ）のｔｅｒｔ−ブタノール溶液（０．４ｍＬ）及び水（０．４ｍＬ）を投入した。フェノール（５．７ｍｇ、０．０６ｍｍｏｌ）、ＤＡＢＣＯ（２０．３ｍｇ、０．１８ｍｍｏｌ）及びホルムアルデヒド（３７％水溶液、２４μＬ、０．２４ｍｍｏｌ）を順次加えた。得られた溶液を密封し、５５℃で２９時間加熱した。反応物を室温に冷却し、水（６ｍＬ）とＤＣＭ／ＭｅＯＨ（１０：１）で分配した。有機層を分離し、水層をＤＣＭ／ＭｅＯＨ（１０：１）でさらに２回抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＭｅＯＨ０〜３．５％含有ＤＣＭ）で精製し、１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシ−１−ナフタレニル）−２，１−ベンゾチアゾール−３−イル）−１−ピペラジニル）−２−（ヒドロキシメチル）−２−プロペン−１−オンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ８．１２ （ｓ、１Ｈ）、７．９４ （ｄ、Ｊ ＝ ８．２ Ｈｚ、１Ｈ）、７．４７−７．５５ （ｍ、２Ｈ）、７．２５−７．３４ （ｍ、２Ｈ）、７．１９ （ｄ、Ｊ ＝ ２．５ Ｈｚ、１Ｈ）、５．４３ （ｂｒ． ｓ、１Ｈ）、５．２０ （ｂｒ． ｓ、１Ｈ）、５．１４ （ｔ、Ｊ ＝ ５．８ Ｈｚ、１Ｈ）、４．１２ （ｄ、Ｊ ＝ ５．７ Ｈｚ、２Ｈ）、３．９４ （ｓ、３Ｈ）、３．７８−３．８５ （ｍ、４Ｈ）、３．５４−３．６６ （ｍ、４Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５１２．０。 Examples 18-1 to 18-3
1- (4- (5-Chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2- (hydroxymethyl)- 2-Propene-1-on. (Example 18-1) and 2- (bromomethyl) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) ) -1-Piperadinyl) -2-propen-1-one (Example 18-2) and 1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2, 1-Benzothiazole-3-yl) -1-piperazinyl) -2- (hydroxymethyl) -2-propen-1-one (Example 18-3)

Step 1: 1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2- (hydroxy) Methyl) -2-propene-1-one.
In a vial, 1- (4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2- A tert-butanol solution (0.4 mL) and water (0.4 mL) of en-1-one (intermediate O, 29 mg, 0.06 mmol) were added. Phenol (5.7 mg, 0.06 mmol), DABCO (20.3 mg, 0.18 mmol) and formaldehyde (37% aqueous solution, 24 μL, 0.24 mmol) were added sequentially. The resulting solution was sealed and heated at 55 ° C. for 29 hours. The reaction was cooled to room temperature and partitioned between water (6 mL) and DCM / MeOH (10: 1). The organic layer was separated and the aqueous layer was extracted twice more with DCM / MeOH (10: 1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0-3.5% MeOH) and 1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2, 1-Benzothiazole-3-yl) -1-piperazinyl) -2- (hydroxymethyl) -2-propen-1-one was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.47-7.55 (m, 2H) , 7.25-7.34 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H), 5.43 (br. S, 1H), 5.20 (br. S, 1H) ), 5.14 (t, J = 5.8 Hz, 1H), 4.12 (d, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.78-3.85 (M, 4H), 3.54-3.66 (m, 4H). m / z (ESI) M + H: 512.0.

Step 2: 2- (Bromomethyl) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) ) -2-Propen-1-one and 1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1- Piperazinyl) -2- (hydroxymethyl) -2-propen-1-one.
At 0 ° C, 1- (4- (5-chloro-7-fluoro-6- (3-methoxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2- Boron tribromide solution (1.0 M hexane solution, 167 μL, 0.17 mmol) in 1,2-dichloroethane solution (4 mL) of (hydroxymethyl) -2-propen-1-one (17.1 mg, 0.033 mmol). Was added dropwise with a syringe. The resulting slurry was quenched with saturated aqueous NaHCO ₃ (5 mL) was stirred 40 min at 0 ° C.. The mixture was extracted twice with a 4: 1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM containing 0 to 7% MeOH) to obtain two products.

First elution peak: 2- (bromomethyl) -1- (4- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine- 1-Il) Propa-2-en-1-on. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (br. S, 1H), 8.13 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7 .40-7.47 (m, 1H), 7.19-7.29 (m, 3H), 7.07 (d, J = 2.4 Hz, 1H), 5.78 (s, 1H), 5.41 (s, 1H), 4.38 (s, 2H), 3.84-3.93 (m, 4H), 3.62-3.72 (m, 4H). m / z (ESI) M + H: 560.0

Second elution peak: 1- (4- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) -2 -(Hydroxymethyl) propa-2-ene-1-one. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (br. S, 1H), 8.11 (s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7 .37-7.48 (m, 1H), 7.17-7.28 (m, 3H), 7.07 (d, J = 2.4 Hz, 1H), 5.43 (br. S, 1H) ), 5.20 (br. S, 1H), 5.07-5.14 (m, 1H), 4.12 (br. S, 2H), 3.78-3.86 (m, 4H), 3.57-3.66 (m, 4H). m / z (ESI) M + H: 498.0

ステップ１：４−（５−クロロ−７−フルオロ−６−（５−メトキシ−１Ｈ−インダゾール−７−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
中間体Ｄ（２３２ｍｇ、０．５１ｍｍｏｌ）と、５−メトキシ−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インダゾール（５３５ｍｇ、１．９５ｍｍｏｌ、下記合成を参照のこと）と炭酸セシウム（６３６ｍｇ、１．９５ｍｍｏｌ）とを１，４−ジオキサン（８ｍＬ）と水（２ｍＬ）との混合液に溶解させたスラリーをアルゴン流で脱気した。テトラキス（トリフェニルホスフィン）パラジウム（５９ｍｇ、０．０５ｍｍｏｌ）を加え、混合物を再度アルゴン流で脱気した。反応混合物を密封し、１００℃で１８時間加熱した。反応物を室温に冷却し、食塩水（４０ｍＬ）とＥｔＯＡｃで分配した。水層をＥｔＯＡｃで２回抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＤＣＭ０〜４．５％／ＭｅＯＨ）で精製し、４−（５−クロロ−７−フルオロ−６−（５−メトキシ−１Ｈ−インダゾール−７−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルを得た。ＬＣＭＳ−ＥＳＩ （陽イオン） ｍ／ｚ： ５１８．２ （Ｍ＋Ｈ）^＋。 ^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ １２．９０ （ｂｒ． ｓ、１Ｈ）、８．０６ （ｓ、１Ｈ）、８．０３ （ｓ、１Ｈ）、７．３１ （ｄ、Ｊ ＝ １．４ Ｈｚ、１Ｈ）、６．９９ （ｄ、Ｊ ＝ ２．２ Ｈｚ、１Ｈ）、３．８３ （ｓ、３Ｈ）、３．６１−３．６９ （ｍ、４Ｈ）、３．５４−３．６０ （ｍ、４Ｈ）、１．４５ （ｓ、９Ｈ）。 Examples 19-1 to 19-3
1- (4- (5-Chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-Propen-1-one (Example 19-1) and 1- (4- (5-chloro-7-fluoro-6- (5-hydroxy-1-methyl-1H-indazole-7-yl))- 2,1-Benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one (Example 19-2) and 1- (4- (5-chloro-7-fluoro-6- (5)) -Hydroxy-2-methyl-2H-indazole-7-yl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one (Example 19-3)

Step 1: 4- (5-Chloro-7-fluoro-6- (5-methoxy-1H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl.
Intermediate D (232 mg, 0.51 mmol) and 5-methoxy-7- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (535 mg, 1 A slurry of .95 mmol (see synthesis below) and cesium carbonate (636 mg, 1.95 mmol) dissolved in a mixture of 1,4-dioxane (8 mL) and water (2 mL) is degassed with an argon stream. did. Tetrakis (triphenylphosphine) palladium (59 mg, 0.05 mmol) was added and the mixture was degassed again with an argon stream. The reaction mixture was sealed and heated at 100 ° C. for 18 hours. The reaction was cooled to room temperature and partitioned between saline (40 mL) and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM0-4.5% / MeOH) and 4- (5-chloro-7-fluoro-6- (5-methoxy-1H-indazole-7-yl) benzo [ c] Isothiazole-3-yl) piperazine-1-carboxylate tert-butyl was obtained. LCMS-ESI (cation) m / z: 518.2 (M + H) ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (br. S, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.31 (d, J = 1.4 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H), 3.61-3.69 (m, 4H), 3.54- 3.60 (m, 4H), 1.45 (s, 9H).

５−メトキシ−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インダゾール。
７−ブロモ−５−メトキシ−１Ｈ−インダゾール（１．００ｇ、４．４０ｍｍｏｌ、Ａｒｋ Ｐｈａｒｍ Ｉｎｃ．Ａｒｌｉｎｇｔｏｎ Ｈｅｉｇｈｔｓ、ＩＬ、ＵＳＡ）と、酢酸カリウム（１．３０ｇ、１３．２ｍｍｏｌ）とビス（ピナコラト）ジボロン（１．２３ｇ、４．８４ｍｍｏｌ）との１，４−ジオキサン懸濁液（１８ｍＬ）をアルゴン流で脱気した。［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ｉｉ）ジクロロメタン錯体（１０８ｍｇ、０．１３ｍｍｏｌ）を加え、再度アルゴン流で脱気した。反応混合物を密封し、８０℃で２日間加熱した。反応物を室温に冷却し、水（５０ｍＬ）とＥｔＯＡｃで分配した。水層をＥｔＯＡｃで２回抽出し、合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＥｔＯＡｃ２〜６５％／ヘプタン）で精製し、５−メトキシ−７−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インダゾールを得た。ＬＣＭＳ−ＥＳＩ （陽イオン） ｍ／ｚ： ２７５．１ （Ｍ＋Ｈ）^＋。

5-Methoxy-7- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole.
7-Bromo-5-methoxy-1H-indazole (1.00 g, 4.40 mmol, Ark Pharm Inc. Arlington Heights, IL, USA), potassium acetate (1.30 g, 13.2 mmol) and bis (pinacolato) diborone. A suspension of 1,4-dioxane (18 mL) with (1.23 g, 4.84 mmol) was degassed with an argon stream. [1,1'-Bis (diphenylphosphino) ferrocene] Dichloropalladium (ii) dichloromethane complex (108 mg, 0.13 mmol) was added, and the mixture was degassed again with an argon stream. The reaction mixture was sealed and heated at 80 ° C. for 2 days. The reaction was cooled to room temperature and partitioned with water (50 mL) and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 2-65% / heptane) and 5-methoxy-7- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). -1H-Indazole was obtained. LCMS-ESI (cation) m / z: 275.1 (M + H) ⁺ .

Step 2: 4- (5-Chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylic acid tert-butyl and 4- (5-chloro-7-fluoro-6- (5-methoxy-2-methyl-2H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylic acid Methoxy-butyl acid.
4- (5-Chloro-7-fluoro-6- (5-methoxy-1H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (115 mg, 0) Sodium hydride (60% mineral oil dispersion, 44.5 mg, 1.1 mmol) was added to a THF solution (5 mL) of .22 mmol). After 10 minutes, iodomethane (69 μL, 1.1 mmol) was added and the reaction was stirred at room temperature for an additional 15 minutes before partitioning with saturated aqueous ammonium chloride solution (10 mL) and DCM. The aqueous layer was extracted twice with DCM and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to concentrate 4- (5-chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole). -7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl and 4- (5-chloro-7-fluoro-6- (5-methoxy-2-methyl-2H-) A mixture with tert-butyl indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate was obtained. The crude mixture was used in subsequent steps without purification. LCMS-ESI (cation) m / z: 532.0 (M + H) ⁺ .

Step 3: 5-Chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) -3- (piperazine-1-yl) benzo [c] isothiazole (intermediate J) ) And 5-Chloro-7-fluoro-6- (5-methoxy-2-methyl-2H-indazole-7-yl) -3- (piperazine-1-yl) benzo [c] isothiazole (intermediate K) ..
4- (5-Chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl And 4- (5-chloro-7-fluoro-6- (5-methoxy-2-methyl-2H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylic acid tert- Trifluoroacetic acid (484 μL, 6.5 mmol) was added via a syringe to a crude mixture of a DCM solution (6 mL) of a mixture of butyl (143 mg). The resulting solution was stirred at room temperature for 25 minutes and then concentrated. The residue was purified by silica gel chromatography (eluent: DCM0-25% / MeOH).

First elution peak: 5-chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) -3- (piperazine-1-yl) benzo [c] isothiazole mono -TFA salt (intermediate J). LCMS-ESI (cation) m / z: 432.0 (M + H) ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 8.03 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 6.99 (D, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.67-3.76 (m, 4H), 3.56 (s, 3H), 3.36-3. 42 (m, 4H).

Second elution peak: 5-chloro-7-fluoro-6- (5-methoxy-2-methyl-2H-indazole-7-yl) -3- (piperazine-1-yl) benzo [c] isothiazole mono -TFA salt (intermediate K). LCMS-ESI (cation) m / z: 432.0 (M + H) ⁺ .

Step 4: 1- (4- (5-Chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) -2,1-benzothiazole-3-yl) -1 − Piperazinyl) -2-propene-1-one.
DiPEA (104 μL, 0.60 mmol) followed by acryloyl chloride (24 μL, 0.30 mmol) in a slurry of DCM solution (5 mL) of ice-cold mono-TFA salt of intermediate J (108 mg, 0.20 mmol) with a syringe. Dropped. The resulting solution was stirred at 0 ° C. for 3 hours, then the reaction was stopped with saturated aqueous NaHCO ₃ solution (15 mL) and extracted twice with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM0-7% / MeOH) and 1- (4- (5-chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7). -Il) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one was obtained. LCMS-ESI (cation) m / z: 486.0 (M + H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 8.02 (s, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.99 (D, J = 2.4 Hz, 1H), 6.85 (dd, J = 16.6, 10.6 Hz, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.76 (dd, J = 10.5, 2.3 Hz, 1H), 3.85-3.95 (m, 4H), 3.84 (s, 3H), 3.62-3 .72 (m, 4H), 3.56 (s, 3H).

Step 5: 1- (4- (5-chloro-7-fluoro-6- (5-hydroxy-1-methyl-1H-indazole-7-yl) -2,1-benzothiazole-3-yl) -1 − Piperazinyl) -2-propene-1-one.
1- (4- (5-chloro-7-fluoro-6- (5-methoxy-1-methyl-1H-indazole-7-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) Boron tribromide solution (1.0 M hexane solution, 746 μL, 0.75 mmol) in ice-cooled 1,2-dichloroethane solution (5 mL) of propa-2-ene-1-one (72.5 mg, 0.15 mmol) Was added dropwise with a syringe. The resulting slurry was stirred at 0 ° C. for 3.75 hours, then the reaction was stopped with saturated aqueous NaHCO ₃ solution (5 mL) and extracted twice with a 4: 1 mixture of DCM / MeOH. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM 0-6% / MeOH) and 1- (4- (5-chloro-7-fluoro-6- (5-hydroxy-1-methyl-1H-indazole-7). -Il) benzo [c] isothiazole-3-yl) piperazine-1-yl) propa-2-ene-1-one was obtained. LCMS-ESI (cation) m / z: 472.0 (M + H) ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.12 (d, J = 2. 2 Hz, 1H), 6.81-6.91 (m, 2H), 6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.76 (dd, J = 10.4) , 2.4 Hz, 1H), 3.81-3.94 (m, 4H), 3.62-3.70 (m, 4H), 3.52 (s, 3H).

1- (4- (5-chloro-7-fluoro-6- (5-hydroxy-2-methyl-2H-indazole-7-yl) -2,1-benzothiazole-3-yl) -1-piperazinyl) For the synthesis of -2-propene-1-one.

Steps 4 and 5 were carried out as described above using the intermediate K of step 3 and 1- (4- (5-chloro-7-fluoro-6- (5-hydroxy-2-methyl-2H-indazole) -7-yl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one was produced. LCMS-ESI (cation) m / z: 472.0 (M + H) ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 9.28 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 6.95 (d, J = 2. 0 Hz, 1H), 6.77-6.90 (m, 2H), 6.18 (dd, J = 16.7, 2.5 Hz, 1H), 5.76 (dd, J = 10.4) 2, 2.2 Hz, 1H), 4.03 (s, 3H), 3.80-3.94 (m, 4H), 3.58-3.66 (m, 4H).

ステップ１：４−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）−２−メチレンブタン−１−オン。
４−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−２−メチレンブタン酸（１０１ｍｇ、０．２９ｍｍｏｌ、Ｐｉｈｋｏ、Ｐ．Ｍ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００６，７１，２５３８−２５４１及びＧｒｅａｎｅｙ，Ｍ．Ｆ．，Ｏｒｇ．Ｌｅｔｔ．，２００７，９，１９３１−１９３４に従って調製）のＤＣＭ溶液（２ｍＬ）に塩化オキサリル（０．２１ｍＬ、０．４３ｍｍｏｌ）の２Ｍ溶液を０℃で加え、次いで触媒量のＤＭＦ（５μＬ）を加えた。反応混合物を室温まで昇温させ、２時間撹拌した。反応混合物を減圧濃縮した後、ＤＣＭ（１ｍＬ）で希釈し、５−クロロ−７−フルオロ−６−（３−メトキシナフタレン−１−イル）−３−（ピペラジン−１−イル）ベンゾ［ｃ］イソチアゾール（中間体Ｎ、１２２ｍｇ、０．２９ｍｍｏｌ）、トリエチルアミン（０．２０ｍＬ、１．４３ｍｍｏｌ）、及びＤＣＭ（２ｍＬ）の溶液に加えた。反応混合物を室温まで昇温させ、ＤＭＡＰ（２ｍｇ、０．０１６ｍｍｏｌ）を加えた。反応混合物を室温で１５時間撹拌し、その後、減圧濃縮してシリカゲルカラムクロマトグラフィー（溶離液：０〜５０％ＥｔＯＡｃ：ヘプタン）で精製し、４−（（ｔｅｒｔ−ブチルジフェニルシリル）オキシ）−１−（４−（５−クロロ−７−フルオロ−６−（３−メトキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−イル）−２−メチレンブタン−１−オンが得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ８．０６ （ｓ、１Ｈ）、７．９４ （ｄ、Ｊ ＝ ８．０ Ｈｚ、１Ｈ）、７．６３−７．６１ （ｍ、４Ｈ）、７．５２−７．４９ （ｍ、２Ｈ）、７．４７−７．４０ （ｍ、６Ｈ）、７．３３−７．２８ （ｍ、２Ｈ）、７．２０−７．１９ （ｍ、１Ｈ）、５．３７ （ｓ、１Ｈ）、５．２４ （ｓ、１Ｈ）、３．９４ （ｓ、３Ｈ）、３．８３−３．７６ （ｍ、６Ｈ）、３．５３ （ｂｒ ｓ、２Ｈ）、３．３１ （ｓ、４Ｈ）、１．０１ （ｓ、９Ｈ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ７６４。 Example 20
1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -4-hydroxy-2-methylidene -1-Butanone

Step 1: 4-((tert-butyldiphenylsilyl) oxy) -1-(4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3) -Il) Piperazine-1-yl) -2-methylenebutane-1-one.
4-((tert-Butyldiphenylsilyl) oxy) -2-methylenebutanoic acid (101 mg, 0.29 mmol, Pihko, PM, J. Org. Chem., 2006, 71, 2538-2541 and Greeney, M. Add a 2M solution of oxalyl chloride (0.21 mL, 0.43 mmol) to a DCM solution (2 mL) of F., Org. Lett., 2007, 9, 1931-1934) at 0 ° C., then in catalytic amounts. DMF (5 μL) was added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM (1 mL), and 5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) -3- (piperazine-1-yl) benzo [c]. It was added to a solution of isothiazole (Intermediate N, 122 mg, 0.29 mmol), triethylamine (0.20 mL, 1.43 mmol), and DCM (2 mL). The reaction mixture was warmed to room temperature and DMAP (2 mg, 0.016 mmol) was added. The reaction mixture is stirred at room temperature for 15 hours, then concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 0-50% EtOAc: heptane) to 4-((tert-butyldiphenylsilyl) oxy) -1. -(4- (5-Chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-1-yl) -2-methylenebutane-1- Got on. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.63-7.61 (m, 4H) , 7.52-7.49 (m, 2H), 7.47-7.40 (m, 6H), 7.33-7.28 (m, 2H), 7.20-7.19 (m, 1H), 5.37 (s, 1H), 5.24 (s, 1H), 3.94 (s, 3H), 3.83-3.76 (m, 6H), 3.53 (br s, 2H), 3.31 (s, 4H), 1.01 (s, 9H). m / z (ESI) M + H: 764.

Step 2: 1- (4- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -4-hydroxy- 2-Methylidene-1-butanone.
4-((tert-Butyldiphenylsilyl) oxy) -1-(4- (5-chloro-7-fluoro-6- (3-methoxynaphthalene-1-yl) benzo [c] isothiazole-3-yl)) Add 2M of a DCM solution of BBr ₃ (0.28 mL, 0.56 mmol) to a solution of piperazine-1-yl) -2-methylenebutane-1-one (85 mg, 0.11 mmol) and DCM (2 mL) at 0 ° C. It was. The reaction of the reaction mixture was stopped with water, concentrated under reduced pressure and purified by silica gel column chromatography (eluted with heptane 0-50% / EtOAc: EtOH (3: 1)) and purified by 1- (4- (5-chloro-). 7-Fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -4-hydroxy-2-methylidene-1-butanone was obtained. ^{1 1} H NMR (400 MHz, DMSO-d6) δ 9.93 (br s, 1H), 8.11 (s, 1H), 7.80 (d, J = 12 Hz, 1H), 7.43 (m) , 1H), 7.26-7.20 (m, 3H), 7.07 (s, 1H), 5.32 (s, 1H), 5.16 (s, 1H), 3.83 (br s) , 4H), 3.63 (br s, 4H), 3.53 (t, J = 8.0 Hz, 2H), 2.42 (t, J = 8.0 Hz, 2H). ¹⁹ FNMR (377 MHz, DMSO-d ₆ ) δ-123.8 (s, 1F). m / z (ESI) M + H: 512.

７−メトキシ−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノリン（合成下記）を使用し、中間体Ｄから方法１によって１−（４−（５−クロロ−７−フルオロ−６−（７−ヒドロキシ−５−キノリニル）−２，１−ベンゾチアゾール−３−イル）−１−ピペラジニル）−２−プロペン−１−オンを作製し、その際、以下を変更した：ステップ７では、Ｓ−Ｐｈｏｓ Ｐｄ Ｇ３、炭酸カリウム水溶液、及びＤＭＥを使用し、ステップ８−１では、ＴＦＡ／ＤＣＭを使用し、ステップ８−２では、溶媒にＤＣＥを使用し、ステップ８−３では、三臭化ホウ素溶液（１．０Ｍ ＤＣＥ溶液）を使用して１−（４−（５−クロロ−７−フルオロ−６−（７−ヒドロキシ−５−キノリニル）−２，１−ベンゾチアゾール−３−イル）−１−ピペラジニル）−２−プロペン−１−オンが得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＣＤＣｌ_３） δ ８．８１ （ｄｄ、Ｊ ＝ ４．２、１．３ Ｈｚ、１ Ｈ） ７．７２ − ７．７８ （ｍ、２ Ｈ） ７．６４ （ｓ、１ Ｈ） ７．２８ （ｄ、Ｊ ＝ ２．２ Ｈｚ、１ Ｈ） ７．１６ （ｄｄ、Ｊ ＝ ８．４、４．３ Ｈｚ、１ Ｈ） ６．５６ − ６．６６ （ｍ、１ Ｈ） ６．４０ （ｄｄ、Ｊ ＝ １６．８、１．６ Ｈｚ、１ Ｈ） ５．７８ − ５．８７ （ｍ、１ Ｈ） ４．０１ （ｂｒ． ｓ．、２ Ｈ） ３．８９ （ｂｒ． ｓ．、２ Ｈ） ３．５０ − ３．６０ （ｍ、４ Ｈ）。 ^１９Ｆ ＮＭＲ （３７６ ＭＨｚ、ＣＤＣｌ_３） δ −１２１．３３ （ｓ、１ Ｆ）。 ＭＳ （ＥＳＩ、＋ｖｅ） ｍ／ｚ： ４６９．１ （Ｍ ＋ １）^＋。 Example 21
1- (4- (5-chloro-7-fluoro-6- (7-hydroxy-5-quinolinyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene-1-one

7-Methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline (synthesis below) was used and 1- (4) from intermediate D by method 1. -(5-Chloro-7-fluoro-6- (7-hydroxy-5-quinolinyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one was prepared. In doing so, the following changes were made: S-Phos Pd G3, aqueous potassium carbonate solution, and DME were used in step 7, TFA / DCM was used in step 8-1, and DCE was used as the solvent in step 8-2. In step 8-3, 1- (4- (5-chloro-7-fluoro-6- (7-hydroxy-5-quinolinyl)) using a boron tribromide solution (1.0 M DCE solution) was used. ) -2,1-Benzothiazole-3-yl) -1-piperazinyl) -2-propen-1-one was obtained. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ 8.81 (dd, J = 4.2, 1.3 Hz, 1 H) 7.72-7.78 (m, 2 H) 7.64 (s, 1 H) 7.28 (d, J = 2.2 Hz, 1 H) 7.16 (dd, J = 8.4, 4.3 Hz, 1 H) 6.56-6.66 (m, 1) H) 6.40 (dd, J = 16.8, 1.6 Hz, 1 H) 5.78-5.87 (m, 1 H) 4.01 (br. S., 2 H) 3.89 (Br. S., 2H) 3.50-3.60 (m, 4H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-121.33 (s, 1 F). MS (ESI, + ve) m / z: 469.1 (M + 1) ⁺ .

７−メトキシ−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノリン。
５−ブロモ−７−メトキシキノリン（０．４０７ｇ、１．７１ｍｍｏｌ、ＯｘＣｈｅｍ、Ｗｏｏｄ Ｄａｌｅ、ＩＬ、ＵＳＡ）、４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ（１，３，２−ジオキサボロラン）（０．９１２ｇ、３．５９ｍｍｏｌ）、ＰｄＣｌ_２（ｄｐｐｆ）（０．０５１ｇ、０．０７０ｍｍｏｌ）、及び酢酸カリウム（０．５０３ｇ、５．１３ｍｍｏｌ）のＤＭＦ溶液（９ｍＬ）を９０℃で１時間撹拌し、その後、１００℃で４５分間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）で希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した（７５ｍＬ、２回）。有機層を分離し、無水Ｎａ_２ＳＯ_４で乾燥させて減圧濃縮した。粗生成物をシリカに吸着させ、カラムクロマトグラフィー（シリカゲル、ヘプタン０〜８０％／ＥｔＯＡｃ）で精製し、７−メトキシ−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）キノリンが得られた。ＭＳ （ＥＳＩ、＋ｖｅ） ｍ／ｚ： ２８６．１ （Ｍ ＋ １）^＋。

7-Methoxy-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) quinoline.
5-Bromo-7-methoxyquinoline (0.407 g, 1.71 mmol, OxChem, Wood Dale, IL, USA), 4,4,4', 4', 5,5,5', 5'-octamethyl-2 , 2'-bi (1,3,2-dioxaborolane) (0.912 g, 3.59 mmol), PdCl ₂ (dppf) (0.051 g, 0.070 mmol), and potassium acetate (0.503 g, 5.13 mmol). ) DMF solution (9 mL) was stirred at 90 ° C. for 1 hour, and then at 100 ° C. for 45 minutes. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (75 mL, twice). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The crude product is adsorbed on silica gel, purified by column chromatography (silica gel, heptane 0-80% / EtOAc) and 7-methoxy-5- (4,5,5-tetramethyl-1,3,2). -Dioxaborolan-2-yl) quinoline was obtained. MS (ESI, + ve) m / z: 286.1 (M + 1) ⁺ .

０℃にて、４−アクリロイル−１−（５−クロロ−７−フルオロ−６−（３−ヒドロキシナフタレン−１−イル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−２−カルボン酸メチル（実施例７−３、０．０２２ｇ、０．０４２ｍｍｏｌ）のＴＨＦ／ＥｔＯＨ溶液（１：１；６ｍＬ）にＮａＯＨ（５Ｎ水溶液；１．０ｍＬ、５．０ｍｍｏｌ）を加え、得られた混合物を０℃で５分間撹拌した。反応物を５Ｎ ＨＣｌで０℃にて酸性化し、ＥｔＯＡｃで抽出して、ＨＰＬＣで精製し、１−（５−クロロ−７−フルオロ−６−（３−ヒドロキシ−１−ナフタレニル）−２，１−ベンゾチアゾール−３−イル）−４−（２−プロペノイル）−２−ピペラジンカルボン酸が得られた。ｍ／ｚ （ＥＳＩ、＋ｖｅ） ５１２．０ （Ｍ＋Ｈ）^＋。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ３．１４ − ３．２８ （ｍ、１ Ｈ） ３．５２ − ３．８７ （ｍ、３ Ｈ） ４．１５ − ５．０３ （ｍ、２ Ｈ） ５．１５ − ５．２３ （ｍ、１ Ｈ） ５．７７ − ５．８３ （ｍ、１ Ｈ） ６．１３ − ６．２４ （ｍ、１ Ｈ） ６．８６ （ｂｒ． ｓ．、１ Ｈ） ７．０６ − ７．１２ （ｍ、１ Ｈ） ７．２０ − ７．３０ （ｍ、３ Ｈ） ７．３８ − ７．４９ （ｍ、１ Ｈ） ７．７６ − ７．８４ （ｍ、１ Ｈ） ８．０７ − ８．１３ （ｍ、１ Ｈ） ９．９８ （ｂｒ． ｓ．、１ Ｈ） １３．４２ （ｂｒ． ｓ．、１ Ｈ）。 Example 22
1- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1-benzothiazole-3-yl) -4- (2-propenoyl) -2-piperazincarboxylic acid

Methyl 4-acryloyl-1- (5-chloro-7-fluoro-6- (3-hydroxynaphthalene-1-yl) benzo [c] isothiazole-3-yl) piperazine-2-carboxylate at 0 ° C. NaOH (5N aqueous solution; 1.0 mL, 5.0 mmol) was added to a THF / EtOH solution (1: 1; 6 mL) of (Example 7-3, 0.022 g, 0.042 mmol), and the resulting mixture was 0. The mixture was stirred at ° C. for 5 minutes. The reaction is acidified with 5N HCl at 0 ° C., extracted with EtOAc, purified by HPLC and 1- (5-chloro-7-fluoro-6- (3-hydroxy-1-naphthalenyl) -2,1 -Benzothiazole-3-yl) -4- (2-propenoyl) -2-piperazincarboxylic acid was obtained. m / z (ESI, + ve) 512.0 (M + H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.14 − 3.28 (m, 1 H) 3.52 − 3.87 (m, 3 H) 4.15 − 5.03 (m, 2 H) 5.15-5.23 (m, 1H) 5.77-5.83 (m, 1H) 6.13-6.24 (m, 1H) 6.86 (br. S., 1H) 7.06-7.12 (m, 1H) 7.20-7.30 (m, 3H) 7.38-7.49 (m, 1H) 7.76-7.84 (m, 1H) m, 1H) 8.07-8.13 (m, 1H) 9.98 (br. S., 1H) 13.42 (br. S., 1H).

実施例２３を、ステップ７の（５−シクロプロピル−１Ｈ−インダゾール−４−イル）ボロン酸（下記合成を参照のこと）を使用し、ステップ８−３を省略して方法１に記載のように作製した。ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４８２．０ （Ｍ＋Ｈ）^＋。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ １２．９２ − １３．１９ （１ Ｈ、ｍ）、８．０２ − ８．２１ （１ Ｈ、ｍ）、７．４７ − ７．６０ （２ Ｈ、ｍ）、７．０２ − ７．０９ （１ Ｈ、ｍ）、６．８０ − ６．９３ （１ Ｈ、ｍ）、６．１５ − ６．２５ （１ Ｈ、ｍ）、５．７１ − ５．８２ （１ Ｈ、ｍ）、３．８０ − ３．９６ （４ Ｈ、ｍ）、３．６０ − ３．７２ （４ Ｈ、ｍ）、１．５５ − １．７４ （１ Ｈ、ｍ）、０．７２ − ０．７９ （２ Ｈ、ｍ）、０．５８ − ０．７１ （２ Ｈ、ｍ）。 Example 23
1-(4- (5-chloro-6- (5-cyclopropyl-1H-indazole-4-yl) -7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2- Propene-1-on

Example 23, as described in Method 1, using step 7 (5-cyclopropyl-1H-indazole-4-yl) boronic acid (see synthesis below), omitting steps 8-3. Made in. m / z (ESI, + ve) 482.0 (M + H) ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.92-13.19 (1 H, m), 8.02-8.21 (1 H, m), 7.47-7.60 (2) H, m), 7.02-7.09 (1 H, m), 6.80-6.93 (1 H, m), 6.15-6.25 (1 H, m), 5.71 −5.82 (1 H, m), 3.80 − 3.96 (4 H, m), 3.60 − 3.72 (4 H, m), 1.55 − 1.74 (1 H,) m), 0.72-0.79 (2 H, m), 0.58-0.71 (2 H, m).

ステップ１：２−ブロモ−１−シクロプロピル−４−フルオロベンゼン。
室温にて、２Ｌ丸底フラスコに２−ブロモ−４−フルオロ−１−ヨードベンゼン（２２ｇ、７３．１ｍｍｏｌ）及びシクロプロピルボロン酸（１２．６ｇ、１４６ｍｍｏｌ）のシクロペンチルメチルエーテル溶液（１．１Ｌ）を加えた。Ｎａ_２ＣＯ_３（２Ｍ水溶液；１８３ｍＬ）を加え、反応物をＮ_２ガスで２０分間脱気した。テトラキス（８．４５ｇ、７．３１ｍｍｏｌ）を加え、反応物を再度Ｎ_２ガスで２０分間脱気した。その後、反応混合物をＮ_２雰囲気下で５Ｌオートクレーブに移し、１３０℃に４０時間加熱した。反応混合物を室温に冷却し、セライトパッドに通してろ過し、ジエチルエーテル（２００ｍＬ）で洗浄した。ろ液に水（５００ｍＬ）を加え、有機層を分離した。水層をジエチルエーテルで抽出し（３００ｍＬ、２回）、合わせた有機層を無水硫酸ナトリウムで乾燥させ、減圧下で蒸発させた。粗物質をシリカゲルのプラグに吸着させ、クロマトグラフィー（シリカゲル、１００％石油エーテル）で精製し、２−ブロモ−１−シクロプロピル−４−フルオロベンゼンを得た。ＧＣ−ＭＳ ｍ／ｚ： ２１４／２１６ ^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＣＤＣｌ_３） δ ７．３６ − ７．２３ （ｍ、１Ｈ）、６．９５ （ｄｔ、Ｊ ＝ ７．０、１．５ Ｈｚ、２Ｈ）、２．０９ （ｄｄｄ、Ｊ ＝ １３．８、８．５、５．４ Ｈｚ、１Ｈ）、１．１２ − ０．８８ （ｍ、２Ｈ）、０．７６ − ０．５０ （ｍ、２Ｈ）。 (5-Cyclopropyl-1H-indazole-4-yl) Boronic acid

Step 1: 2-Bromo-1-cyclopropyl-4-fluorobenzene.
At room temperature, a cyclopentyl methyl ether solution (1.1 L) of 2-bromo-4-fluoro-1-iodobenzene (22 g, 73.1 mmol) and cyclopropylboronic acid (12.6 g, 146 mmol) in a 2 L round bottom flask. Was added. Na ₂ CO ₃ (2M aqueous solution; 183 mL) was added and the reaction was degassed with N ₂ gas for 20 minutes. Tetrakis (8.45 g, 7.31 mmol) was added and the reaction was degassed for 20 minutes again _{N 2} gas. Then, the reaction mixture was transferred to a 5 L autoclave under an N ₂ atmosphere and heated to 130 ° C. for 40 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with diethyl ether (200 mL). Water (500 mL) was added to the filtrate to separate the organic layer. The aqueous layer was extracted with diethyl ether (300 mL, twice) and the combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was adsorbed on a silica gel plug and purified by chromatography (silica gel, 100% petroleum ether) to obtain 2-bromo-1-cyclopropyl-4-fluorobenzene. GC-MS m / z: 214/216 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.23 (m, 1H), 6.95 (dt, J = 7.0, 1.5 Hz) , 2H), 2.09 (ddd, J = 13.8, 8.5, 5.4 Hz, 1H), 1.12-0.88 (m, 2H), 0.76-0.50 (m) , 2H).

Step 2: 2-Bromo-3-cyclopropyl-6-fluorobenzaldehyde.
Under _{N 2} atmosphere 500mL round bottom flask was added 2-bromo-1-cyclopropyl-4-fluorobenzene (6.5 g, 30.2 mmol) in tetrahydrofuran solution of (130 mL). LDA (18.1 mL, 36.3 mmol, 2 M THF solution, 1.2 eq) was added dropwise at −78 ° C. (internal temperature maintained at −65 ° C. to −70 ° C.) and the reaction mixture was stirred for 1 hour. Then DMF (6 mL) was added dropwise to the reaction mixture (internal temperature maintained at −65 ° C. to −70 ° C.) and the reaction was further stirred at −78 ° C. for 3 hours. The reaction was stopped with saturated aqueous ammonium chloride solution (100 mL) and slowly warmed to room temperature. The mixture was diluted with diethyl ether (200 mL), the organic layer was separated and washed with aqueous saline (50 mL, twice). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was adsorbed on a silica gel plug and purified by chromatography (silica gel, EtOAc 0-2% / hexane) to give 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde. GC-MS m / z: 242 ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.43 (d, J = 1.5 Hz, 1H), 7.26-7.12 (m, 1H), 7. 06 (t, J = 9.3 Hz, 1H), 2.15 (td, J = 8.4, 4.3 Hz, 1H), 1.17-0.94 (m, 2H), 0.78 − 0.52 (m, 2H).

Step 3: 4-Bromo-5-cyclopropyl-1H-indazole.
An ethylene glycol solution (40 mL) of 2-bromo-3-cyclopropyl-6-fluorobenzaldehyde (4 g, 16.5 mmol) and hydrazine hydrate (4.0 mL, 82 mmol) was added to a 100 mL sealed tube. The reaction was stirred for 2 hours at 90 ° C. and then heated to 150 ° C. for 16 hours. The reaction mixture was cooled to room temperature and ice water (40 mL) and EtOAc (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (40 mL, twice). The combined organic layers were washed with water (40 mL, twice), washed with aqueous saline solution (40 mL), dried over aqueous anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was adsorbed on a silica gel plug and purified by chromatography (silica gel, EtOAc 0-20% / hexane) to give 4-bromo-5-cyclopropyl-1H-indazole. The compound was purified by reverse phase preparative liquid chromatography (YMC: C ₁₈ , 150 × 20 mm, 5 μm; mobile phase: water containing 0.1% TFA and acetonitrile; flow rate: 15 mL / min) to obtain a pure compound. Obtained. MS (ESI positive ion) m / z: 237 / 239.0 (M + 1). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ 13.31 (s, 1H), 7.97 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.97 (D, J = 8.6 Hz, 1H), 2.21 (tt, J = 8.5, 5.3 Hz, 1H), 1.24-0.87 (m, 2H), 0.93- 0.33 (m, 2H).

Step 4: 5-cyclopropyl-1H-indazole-4-yl) boronic acid.
A 1,4-dioxane solution (25 mL) of 4-bromo-5-cyclopropyl-1H-indazole (0.62 g, 2.6 mmol) and bis (pinacolato) diboron (0.996 g, 3.92 mmol) in a 100 mL round bottom flask. ) was added and, after addition of potassium acetate (0.77 g, 7.84 mmol), and the reaction mixture was degassed for 10 minutes with _{N 2} gas. PdCl ₂ (dppf). In addition DCM adduct (0.213 g, 0.261 mmol) to the reaction mixture, it was degassed for 10 minutes with the reaction mixture again _{N 2} gas, and heated 16 h to 100 ° C.. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, the crude material was adsorbed on a silica gel plug, and purified by chromatography (silica gel, EtOAc 0-50% / hexane). The compound was further purified by reverse phase preparative liquid chromatography (Grace column; MeCN 0-70% / water) to obtain 5-cyclopropyl-1H-indazole-4-yl) boronic acid. MS (ESI positive ion) m / z: 285.2 (M + 1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.13 (q, J = 1.3 Hz, 1H), 7.50 (d, J = 8.7 Hz) , 1H), 6.83 (dd, J = 8.8, 1.4 Hz, 1H), 2.78-2.60 (m, 1H), 1.38 (d, J = 1.4 Hz, 12H), 1.07-0.85 (m, 2H), 0.75-0.48 (m, 2H).

ステップ１：１−（５−クロロ−７−フルオロ−３−（ピペラジン−１−イル）ベンゾ［ｃ］イソチアゾール−６−イル）−Ｎ−メチルイソキノリン−３−アミン。
０℃にて、４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｄ、３０ｍｇ、０．０６７ｍｍｏｌ）のテトラヒドロフラン溶液（０．６ｍＬ）にイソプロピルマグネシウムクロリドの溶液（２．０Ｍテトラヒドロフラン溶液、０．０５０ｍＬ、０．１００ｍｍｏｌ）を加えた。混合物を５分間撹拌してから、塩化亜鉛（１．９Ｍ ２−メチルテトラヒドロフラン溶液、０．０５３ｍＬ、０．１００ｍｍｏｌ）を加え、反応混合物を室温に昇温させ、４０分間撹拌した。その後、反応混合物をＳｐｈｏｓ Ｐｄ Ｇ３（５．７６ｍｇ、６．６６μｍｏｌ）及び（１−ブロモイソキノリン−３−イル）（メチル）カルバミン酸ｔｅｒｔ−ブチル（２４．７ｍｇ、０．０７３ｍｍｏｌ、下記合成を参照のこと）が入ったバイアルに移し、７０℃に一晩加熱した。粗反応物を飽和ＮＨ_４Ｃｌ水溶液（５０ｍＬ）及びＥｔＯＡｃ（５０ｍＬ）で希釈した。有機層を分離し、Ｎａ_２ＳＯ_４で乾燥させ、ろ過して濃縮した。ＭｅＯＨ６〜２０％含有ＤＣＭで溶出させるシリカゲルカラムクロマトグラフィーで精製し、１−（５−クロロ−７−フルオロ−３−（ピペラジン−１−イル）ベンゾ［ｃ］イソチアゾール−６−イル）−Ｎ−メチルイソキノリン−３−アミンが得られた。ｍ／ｚ （ＥＳＩ、＋ｖｅ） ４２８．１ （Ｍ＋Ｈ）^＋。 Example 24
1- (4- (5-Chloro-7-fluoro-6- (3- (methylamino) -1-isoquinolinyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene- 1-on

Step 1: 1- (5-Chloro-7-fluoro-3- (piperazine-1-yl) benzo [c] isothiazole-6-yl) -N-methylisoquinoline-3-amine.
At 0 ° C., tert-butyl 4- (6-bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate (intermediate D, 30 mg, 0.067 mmol). A solution of isopropylmagnesium chloride (2.0 M tetrahydrofuran solution, 0.050 mL, 0.100 mmol) was added to the tetrahydrofuran solution (0.6 mL). The mixture was stirred for 5 minutes, then zinc chloride (1.9 M 2-methyltetrahydrofuran solution, 0.053 mL, 0.100 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 40 minutes. The reaction mixture was then subjected to Sphos Pd G3 (5.76 mg, 6.66 μmol) and (1-bromoisoquinoline-3-yl) (methyl) tert-butyl carbamate (24.7 mg, 0.073 mmol, see synthesis below). It was transferred to a vial containing (that) and heated to 70 ° C. overnight. The crude reaction was diluted with saturated aqueous _NH 4 Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purify by silica gel column chromatography eluting with DCM containing 6-20% MeOH, 1- (5-chloro-7-fluoro-3- (piperazine-1-yl) benzo [c] isothiazole-6-yl) -N -Methylisoquinoline-3-amine was obtained. m / z (ESI, + ve) 428.1 (M + H) ⁺ .

Synthesis of (1-bromoisoquinoline-3-yl) (methyl) tert-butyl carbamate:
At room temperature, sodium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 1.79 mL) was added to a tetrahydrofuran solution (5 mL) of 1-bromoisoquinoline-3-amine (200 mg, 0.897 mmol, Maybridge Chemical Co., Altrincham, UK). 1.79 mmol) was added. The mixture was stirred for 10 minutes and then a solution of Boc-anhydrous (0.208 mL, 0.897 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 5 minutes, then diluted with saturated aqueous _NH 4 Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel column chromatography eluting with heptane containing 0-20% EtOAc gave tert-butyl (1-bromoisoquinoline-3-yl) carbamate. m / z (ESI, + ve) 345.0 (M + Na) ⁺ .

Sodium hydride (60% mineral oil dispersion, 22.52 mg, 0.563 mmol) in tetrahydrofuran solution (3 mL) of tert-butyl (140 mg, 0.433 mmol) carbamic acid (1-bromoisoquinoline-3-yl) at room temperature. ) Was added. The mixture was stirred for 15 minutes and then methyl iodide (0.033 mL, 0.520 mmol) was added. After stirring overnight, the reaction was diluted with saturated aqueous _NH 4 Cl (50 mL) and EtOAc (50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel column chromatography eluting with heptane containing 0-10% EtOAc gave tert-butyl (1-bromoisoquinoline-3-yl) (methyl) carbamate. ^{1 1} H NMR (400 MHz, methanol-d ₄ ) δ 8.25 (d, J = 8.61 Hz, 1H), 7.88-7.95 (m, 2H), 7.79 (t, J = 7.5 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 3.42 (s, 3H), 1.54 (s, 9H). m / z (ESI, + ve) 359.1 (M + H) ⁺ .

Step 2: 1- (4- (5-chloro-7-fluoro-6- (3- (methylamino) -1-isoquinolinyl) -2,1-benzothiazole-3-yl) -1-piperazinyl) -2 -Propene-1-on.
Method 1, the same procedure as in step 8-2. Purification was performed over 15 minutes by silica gel column chromatography eluting with DCM containing 0-14% MeOH. ^{1 1} H NMR (400 MHz, methanol-d ₄ ) δ 7.90 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.43 (t, J = 7.4 Hz) , 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.72-6.84 (m, 1H), 6 .67 (s, 1H), 6.15-6.28 (m, 1H), 5.68-5.81 (m, 1H), 3.87-3.97 (m, 4H), 3.63 (M, 4H), 2.90 (s, 3H). m / z (ESI, + ve) 482.0 (M + H) ⁺ .

Example 25
1- (4- (6- (3-Amino-1-isoquinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene-1-one

Step 1: 4- (6-(3-((tert-butoxycarbonyl) amino) isoquinoline-1-yl) -5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylic acid Tert-Butyl acid acid.
The procedure is the same as in Example 25, Step 1, but instead of the isopropylmagnesium chloride solution, a 1.3 M THF solution of isopropylmagnesium lithium chloride is used, and (1-bromoisoquinoline-3-yl) (methyl) carbamic acid tert. Bis (2-methyl-2-propanol) (1-bromo-3-isoquinolinyl) -2-imide dicarbonate (synthesis below) was used instead of −butyl. m / z (ESI, + ve) 614.2 (M + H) ⁺ .

Synthesis of bis (2-methyl-2-propanil) (1-bromo-3-isoquinolinyl) -2-imide dicarbonate:
Boc-anhydride (3.12 mL, 13.45 mmol) in a DCM solution (50 mL) of 1-bromoisoquinoline-3-amine (1.0 g, 4.48 mmol, Maybridge Chemical Co., Altrincham, UK) at 0 ° C. ) And DMAP (0.055 g, 0.448 mmol) were added. The reaction was warmed to room temperature and stirred overnight. Thereafter, the reaction mixture was diluted with saturated aqueous _NH 4 Cl (100 mL) and DCM (50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel column chromatography eluting with heptane containing 0-10% EtOAc over 15 minutes gives bis (2-methyl-2-propanil) (1-bromo-3-isoquinolinyl) -2-imide dicarbonate. It was. ^{1 1} H NMR (400 MHz, methanol-d ₄ ) δ 8.36 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.77-7 .92 (m, 3H), 1.44 (s, 18H). m / z (ESI, + ve) 267.0 (M + H) ⁺ .

Step 2: 1- (4- (6- (3-Amino-1-isoquinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene- 1-on.
The procedure is the same as in Method 1, Steps 8-1 and 8-2, but in Step 8-1, TFA-containing DCM is used instead of 4M HCl-containing dioxane / MeOH. Purified by silica gel column chromatography eluting with DCM containing 0-12% MeOH. The substance was then subjected to SFC purification (using 17% (20 mM NH ₃ containing MeOH) in a diol column (21.2 x 250 mm, 5 μm) in supercritical CO ₂ (total flow rate was 7 g / min)). , 1- (4- (6- (3-Amino-1-isoquinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propen-1- Got on. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.85 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.39 (t, J = 7.6 Hz) , 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.82 (s, 1H), 6.71 (dd) , J = 10.8, 16.8 Hz, 1H), 6.2 (dd, J = 1.5, 16.8 Hz, 1H), 5.70 (dd, J = 1.5, 10.8) Hz, 1H), 3.82-3.93 (m, 4H), 3.50-3.66 (m, 4H). m / z (ESI, + ve) 468.0 (M + H) ⁺ .

ステップ１：４−（５−クロロ−７−フルオロ−６−（トリブチルスタンニル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル。
４−（６−ブロモ−５−クロロ−７−フルオロベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチル（中間体Ｄ、３２０ｍｇ、０．７１０ｍｍｏｌ）、１，１，１，２，２，２−ヘキサブチルジスタンナン（８２４ｍｇ、１．４２０ｍｍｏｌ）、及びテトラキス（トリフェニルホスフィン）パラジウム（０）（８２ｍｇ、０．０７１ｍｍｏｌ、Ｓｔｒｅｍ Ｃｈｅｍｉｃａｌｓ Ｉｎｃ．、ＮｅｗｂｕｒｙＰｏｒｔ、ＭＡ、ＵＳＡ）のＮ，Ｎ−ジメチルアセトアミド溶液（５ｍＬ）を密封バイアルに入れて電子レンジで１６０℃にて４０分加熱した。反応混合物を飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）、食塩水（５０ｍＬ）及びＥｔＯＡｃ（１００ｍＬ）で希釈した。有機層を分離し、Ｎａ_２ＳＯ_４で乾燥させ、ろ過して濃縮した。ＥｔＯＡｃ０〜３０％含有ヘプタンで溶出させるシリカゲルカラムクロマトグラフィーで精製し、４−（５−クロロ−７−フルオロ−６−（トリブチルスタンニル）ベンゾ［ｃ］イソチアゾール−３−イル）ピペラジン−１−カルボン酸ｔｅｒｔ−ブチルが得られた。ｍ／ｚ （ＥＳＩ、＋ｖｅ） ６６２．２ （Ｍ＋Ｈ）^＋。 Example 26
1- (4- (6- (2-Amino-4-quinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene-1-one

Step 1: tert-butyl 4- (5-chloro-7-fluoro-6- (tributylstannyl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate.
4- (6-Bromo-5-chloro-7-fluorobenzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (intermediate D, 320 mg, 0.710 mmol), 1,1, 1,2,2,2-hexabutyldistannan (824 mg, 1.420 mmol), and tetrakis (triphenylphosphine) palladium (0) (82 mg, 0.071 mmol, Strem Chemicals Inc., NewburyPort, MA, USA). The N, N-dimethylacetamide solution (5 mL) was placed in a sealed vial and heated in a microwave oven at 160 ° C. for 40 minutes. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution (50 mL), saline solution (50 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purify by silica gel column chromatography eluting with heptane containing 0-30% EtOAc and 4- (5-chloro-7-fluoro-6- (tributylstannyl) benzo [c] isothiazole-3-yl) piperazine-1- The tert-butyl carboxylate was obtained. m / z (ESI, + ve) 662.2 (M + H) ⁺ .

Step 2: 2-Methyl-2-propanil 4-(6-(2- (bis (((2-methyl-2-propanyl) oxy) carbonyl) amino) -4-quinolinyl) -5-chloro-7-fluoro -2,1-Benzothiazole-3-yl) -1-piperazin carboxylate.
Di-tert-butyl (4-bromoquinoline-2-yl) -2-imide dicarbonate (19.2 mg, 0.045 mmol, 4-bromoquinoline-2-amine (Ark Pharm Inc. Arlington Heights, IL, USA) ) As a starting material, bis (2-methyl-2-propanol) (1-bromo-3-isoquinolinyl) -2-imide dicarbonate of Example 26), 4- (5-). Chloro-7-fluoro-6- (tributylstannyl) benzo [c] isothiazole-3-yl) piperazine-1-carboxylate tert-butyl (20 mg, 0.030 mmol), tetrakis (triphenylphosphine) palladium (0) (6.99 mg, 6.05 μmol, Strem Chemicals Inc., NewburyPort, MA, USA), copper iodide (I) (1.153 mg, 6.05 μmol) and cesium fluoride (13.79 mg, 0.091 mmol). The DMF solution (0.5 mL) in which the mixture was dissolved was placed in a sealed vial and heated at 60 ° C. for 30 minutes. The crude reaction was diluted with saturated aqueous NaHCO ₃ solution (50 mL) and EtOAc (100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. Purify by silica gel column chromatography eluting with heptane containing 0-50% EtOAc, 2-methyl-2-propanil 4-(6-(2-(bis (((2-methyl-2-propanyl) oxy) carbonyl) carbonyl) amino ) -4-Kinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazin carboxylate was obtained. m / z (ESI, + ve) 714.2 (M + H) ⁺ .

Step 3: 1- (4- (6- (2-Amino-4-quinolinyl) -5-chloro-7-fluoro-2,1-benzothiazole-3-yl) -1-piperazinyl) -2-propene- 1-on.
The procedure is the same as in Method 1, Steps 8-1 and 8-2, but in Step 8-1, TFA-containing DCM is used instead of 4M HCl-containing dioxane / MeOH. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.90 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.42-7.49 (m, 1H) , 7.10 (d, J = 8.0 Hz, 1H), 7.03-7.08 (m, J = 7.6 Hz, 1H), 6.67-6.81 (m, 2H), 6.19 (dd, J = 1.8, 16.6 Hz, 1H) 5.72 (dd, J = 1.8, 10.6 Hz, 1H) 3.87-3.93 (m, 4H), 3.56-3.66 (m, 4H). m / z (ESI, + ve) 468.0 (M + H) ⁺ .

ステップ１：６，７−ジヒドロピリド［２，３−ｄ］ピリダジン−５，８−ジオン。
ヒドラジン（１．２６ｍＬ、４０．２ｍｍｏｌ）を、撹拌した２，３−ピリジンジカルボン酸無水物（４．００ｇ、２６．８ｍｍｏｌ）のエタノール溶液（１００ｍＬ）に加えた。反応混合物を１６時間還流させてから室温に冷却して減圧濃縮し、粗６，７−ジヒドロピリド［２，３−ｄ］ピリダジン−５，８−ジオンが得られ、それを直接次ステップで使用した。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： １６４．１。 Example 27
1- (4- (3- (2-fluoro-6-hydroxyphenyl) -2-methyl-5-(2- (2-propanil) phenyl) pyrido [2,3-d] pyridazine-8-yl)- 1-Pyridazine) -2-propene-1-one

Step 1: 6,7-dihydropyrido [2,3-d] pyridazine-5,8-dione.
Hydrazine (1.26 mL, 40.2 mmol) was added to a stirred ethanol solution (100 mL) of 2,3-pyridinedicarboxylic acid anhydride (4.00 g, 26.8 mmol). The reaction mixture was refluxed for 16 hours, cooled to room temperature and concentrated under reduced pressure to give crude 6,7-dihydropyrido [2,3-d] pyridazine-5,8-dione, which was used directly in the next step. .. m / z (ESI) M + H: 164.1.

Step 2: 5,8-dichloropyrido [2,3-d] pyridazine.
A solution of pyridine (4.57 mL, 53.7 mmol) in crude 6,7-dihydropyrido [2,3-d] pyridazine-5,8-dione (4.38 g, 26.8 mmol) in phosphorus (v) oxychloride. 20.1 mL) was added to the mixture. The reaction mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled and slowly poured into rapidly stirred water (250 mL) at about 10 ° C. The aqueous suspension was stirred for 15 minutes and then extracted with EtOAc (250 mL). The organic layer was separated, washed with brine (200 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing EtOAc 0 to 100%) to give 5,8-dichloropyrido [2,3-d] pyridazine. ^{1 1 1} H NMR (400 MHz, chloroform-d) δ 9.41 (1 H, dd, J = 4.30, 1.56 Hz) 8.65 (1 H, dd, J = 8.41, 1.56) Hz) 8.02 (1 H, dd, J = 8.41, 4.30 Hz). m / z (ESI) M + H: 200.0.

Step 3: 3,5-dichloropyrido [2,3-d] pyridazine-8 (7H) -on and 3,8-dichloropyrido [2,3-d] pyridazine-5 (6H) -on.
N-Chlorosuccinimide (1268 mg, 9.50 mmol, TCI America, Portland, OR, USA) mixed with agitated 5,8-dichloropyrido [2,3-d] pyridazine (950 mg, 4.75 mmol) in acetic acid solution (20 mL). In addition, the reaction mixture was heated to 100 ° C. for 16 hours. Further N-chlorosuccinimide (1268 mg, 9.50 mmol, TCI America, Portland, OR, USA) was added and the reaction mixture was stirred at 100 ° C. for an additional 4 hours. Further N-chlorosuccinimide (634 mg, 4.75 mmol, TCI America, Portland, OR, USA) was added and the reaction mixture was stirred for an additional 4 hours. The reaction mixture was then diluted with water (75 mL) and extracted 3 times with EtOAc (100 mL). The combined organic layers were washed with brine (150 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0-75% EtOAc), 3,5-dichloropyrido [2,3-d] pyridazine-8 (7H) -one compound and 3,8-dichloropyrido [2,3-d] d] A mixture of pyridazine-5 (6H) -one position isomers was obtained. m / z (ESI) M + H: 215.9.

Step 4: 3,5,8-Trichloropyrido [2,3-d] pyridazine.
Pyridine (2.024 mL, 23.79 mmol), 3,5-dichloropyrido [2,3-d] pyridazine-8 (7H) -one and 3,8-dichloropyrido [2,3-d] pyridazine-5 (6H) ) -On (2.57 g, 11.90 mmol) was added to a phosphorus oxychloride solution (8.90 mL, 95 mmol) of the positional isomer mixture. The reaction mixture was stirred at 100 ° C. for 1.5 hours. The reaction mixture was cooled and slowly poured into rapidly stirred water (150 mL) at about 10 ° C. The aqueous suspension was stirred for 15 minutes and then extracted with EtOAc (200 mL). The organic layer was separated, washed with brine (150 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0% to 50% EtOAc) to give 3,5,8-trichloropyrido [2,3-d] pyridazine. ^{1 1} H NMR (400 MHz, chloroform-d) δ 9.27 (1 H, d, J = 2.35 Hz) 8.58 (1 H, d, J = 2.35 Hz). m / z (ESI) M + H: 233.9.

Step 5: 4- (3,5-dichloropyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylate tert-butyl.
1-Boc-piperazine (278 mg, 1.494 mmol) with 3,5,8-trichloropyrido [2,3-d] pyridazine (292 mg, 1.245 mmol) and triethylamine (0.350 mL, 2.491 mmol) Was added to the stirred mixed dimethyl sulfoxide solution (5 mL). The reaction mixture was stirred at room temperature for 3 hours, then diluted with EtOAc (75 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (75 mL). The organic layer was separated, washed with brine (50 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0 to 25% acetone), and 4- (3,5-dichloropyridazine [2,3-dichloropyridazine], which is the first positional isomer of the two positional isomers to be eluted. d] Pyridazine-8-yl) piperazine-1-carboxylate tert-butyl was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ 9.01 (1 H, d, J = 2.54 Hz) 8.43 (1 H, d, J = 2.54 Hz) 4.04-4. 15 (4 H, m) 3.64-3.70 (4 H, m) 1.50 (9 H, s). m / z (ESI) M + H: 384.0.

Step 6: 4- (3-Chloro-5- (2-isopropylphenyl) pyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylate tert-butyl.
4- (3,5-dichloropyrido [2,3-d] pyridazine-8-yl) piperazin-1-carboxylate tert-butyl (199 mg, 0.518 mmol), 2-isopropylphenylboronic acid (93 mg, 0.570 mmol) , Alfa Aesar, HaverHill, MA, USA), Tetrakis (triphenylphosphine) palladium (59.8 mg, 0.052 mmol, Strem Chemicals Inc., NewburyPort, MA, USA), and sodium carbonate (2M aqueous solution, 1.036 mL). , 2.072 mmol) was mixed with 1,4-dioxane (4 mL) under an argon atmosphere. The reaction mixture was stirred at 40 ° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (40 mL). The organic layer was separated, washed with brine (50 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing 0% to 50% EtOAc) to give a mixture of starting material and desired product. The mixture was subjected to the original reaction conditions again with a small amount of 2-isopropylphenylboronic acid (56 mg, 0.342 mmol, Alfa Aesar, Haverhill, MA, USA). The mixture was stirred at 40 ° C. for 16 hours. Further 2-isopropylphenylboronic acid (28 mg, 0.171 mmol, Alfa Aesar, Haverhill, MA, USA) was added and the reaction mixture was stirred for an additional 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (40 mL). The organic layer was separated, washed with brine (50 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0% to 50% EtOAc) and 4- (3-chloro-5- (2-isopropylphenyl) pyrido [2,3-d] pyridazine-8-yl) piperazin-1. Tert-Butyl carboxylate was obtained. ¹ H NMR (400 MHz, chloroform-d) δ 8.95 (1 H, d, J = 2.35 Hz) 7.72 (1 H, d, J = 2.54 Hz) 7.45-7. 53 (2 H, m) 7.26-7.33 (1 H, m) 7.16-7.21 (1 H, m) 4.04-4.23 (4 H, m) 3.66- 3.73 (4 H, m) 2.67 (1 H, spt, J = 6.75 Hz) 1.48 (9 H, s) 1.16 (3 H, d, J = 6.85 Hz) 1.03 (3 H, d, J = 6.85 Hz). m / z (ESI) M + H: 468.2.

Step 7: tert-butyl 4- (3-chloro-5- (2-isopropylphenyl) -2-methylpyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylate.
Methyllithium (1.6 M diethyl ether solution, 0.137 mL, 0.219 mmol) was stirred with 4- (3-chloro-5- (2-isopropylphenyl) pyrido [2,3-d] pyridazine-8-yl). ) Pyridazine-1-carboxylate tert-butyl (93 mg, 0.199 mmol) was added to a solution in tetrahydrofuran (1 mL) at −78 ° C. The reaction mixture was stirred at −78 ° C. for 5 minutes, then warmed to 0 ° C. and stirred for 30 minutes. The reaction mixture was cooled to -78 ° C. and additional methyllithium (1.6 M diethyl ether solution, 0.068 mL, 0.109 mmol) was added. The reaction mixture was stirred at −78 ° C. for 5 minutes, then warmed to 0 ° C. and further stirred for 15 minutes. The reaction of the reaction mixture was stopped with water (20 mL) and extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (20 mL), dried over MgSO _4, vacuum filtered and concentrated to give crude 4- (3-chloro-5- (2-isopropyl-phenyl) -2-methyl-1 , 2-Dihydropyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylate tert-butyl was obtained. m / z (ESI) M + H: 484.3.

4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (45.0 mg, 0.198 mmol) was added to crude 4- (3-chloro-5- (2-). Stirred mixed dichloromethane solution of tert-butyl (96 mg, 0.198 mmol) of isopropylphenyl) -2-methyl-1,2-dihydropyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylate (2 mL) ). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with DCM (30 mL) and washed with water (20 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0-50% EtOAc) and 4- (3-chloro-5- (2-isopropylphenyl) -2-methylpyrido [2,3-d] pyridazine-8-yl). The piperazine-1-carboxylate tert-butyl was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ 7.72 (1 H, s) 7.51-7.55 (2 H, m) 7.32-7.37 (1 H, m) 7.22 − 7.27 (1 H, m) 4.08 − 4.25 (4 H, m) 3.71 − 3.79 (4 H, m) 2.87 (3 H, s) 2.73 (1) H, spt, J = 6.68 Hz) 1.54 (9 H, s) 1.21 (3 H, d, J = 6.85 Hz) 1.07 (3 H, d, J = 6.85) Hz). m / z (ESI) M + H: 482.1.

Step 8: 4- (3- (2-Fluoro-6-Hydroxyphenyl) -5- (2-isopropylphenyl) -2-methylpyrido [2,3-d] pyridazine-8-yl) piperazine-1-carboxylic acid tert-butyl.
4- (3-Chloro-5- (2-isopropylphenyl) -2-methylpyrido [2,3-d] pyridazine-8-yl) piperazin-1-carboxylate tert-butyl (78 mg, 0.162 mmol), ( 2-Fluoro-6-hydroxyphenyl) boronic acid (101 mg, 0.647 mmol, Combi-Blocks), SPhos Pd G3 (14.00 mg, 0.016 mmol) and sodium carbonate (2M aqueous solution, 0.324 mL, 0.647 mmol) Was mixed with 1,2-dimethoxyethane (1 mL) under an argon atmosphere, and then heated at 80 ° C. for 2.5 hours. The reaction mixture was cooled, diluted with EtOAc (30 mL) and washed with water (25 mL). The organic layer was separated, washed with brine (25 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0 to 50% EtOAc) and 4- (3- (2-fluoro-6-hydroxyphenyl) -5- (2-isopropylphenyl) -2-methylpyridazine [2,3]. -D] Pyridazine-8-yl) piperazine-1-carboxylate tert-butyl (66 mg, 0.118 mmol, yield 73.1%) was obtained. m / z (ESI) M + H: 558.2.

Step 9: 3-Fluoro-2- (5- (2-isopropylphenyl) -2-methyl-8- (piperazine-1-yl) pyrido [2,3-d] pyridazine-3-yl) phenol.
Trifluoroacetic acid (0.2 mL, 2.68 mmol) was stirred with 4- (3- (2-fluoro-6-hydroxyphenyl) -5- (2-isopropylphenyl) -2-methylpyridazine [2,3-d]. ] Pyridazine-8-yl) piperazine-1-carboxylate tert-butyl (64 mg, 0.115 mmol) was added to a dichloromethane solution (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM (30 mL) and the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer is separated, dried with sulfonyl ₄ and filtered, then concentrated under reduced pressure and crude 3-fluoro-2- (5- (2-isopropylphenyl) -2-methyl-8- (piperazine-1-yl)). Pyrid [2,3-d] pyridazine-3-yl) phenol was obtained. m / z (ESI) M + H: 458.1.

Step 10: 1- (4- (3- (2-fluoro-6-hydroxyphenyl) -5- (2-isopropylphenyl) -2-methylpyrido [2,3-d] pyridazine-8-yl) piperazine-1 -Il) Propa-2-en-1-on.
Acryloyl chloride (9.45 μl, 0.116 mmol) with 3-fluoro-2- (5- (2-isopropylphenyl) -2-methyl-8- (piperazine-1-yl) pyride [2,3-d]] Pyridazine-3-yl) phenol (53 mg, 0.116 mmol) and triethylamine (0.049 mL, 0.348 mmol) were added to a stirred mixed dichloromethane solution (1 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 10 minutes. The reaction mixture was diluted with DCM (25 mL) and the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing EtOAc 0-100%) and 1- (4- (3- (2-fluoro-6-hydroxyphenyl) -2-methyl-5- (2- (2-propanil)). ) Phenyl) pyrido [2,3-d] pyridazine-8-yl) -1-piperazinyl) -2-propen-1-one was obtained. ¹ H NMR (400 MHz, chloroform-d) δ 9.51 (0.6 H, br s) 8.98 (0.4 H, br s) 7.63 (0.4 H, s) 7.58 (0.6 H, s) 7.35-7.43 (2 H, m) 7.10-7.26 (3 H, m) 6.78 (1 H, dd, J = 16.63, 8) .22 Hz) 6.59-6.71 (2 H, m) 6.36 (1 H, dd, J = 16.82, 1.57 Hz) 5.78 (1 H, dd, J = 10. 56, 1.37 Hz) 4.10-4.38 (4 H, m) 3.80-4.03 (4 H, m) 2.60-2.72 (1 H, m) 2.61 ( 1.2 H, s) 2.59 (1.8 H, s) 0.91 to 1.08 (6 H, m). m / z (ESI) M + H: 512.3.

α−メチルベンジル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、４９２μｌ、０．２４６ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（５．６８ｍｇ、４．９２μｍｏｌ、Ｓｔｒｅｍ Ｃｈｅｍｉｃａｌｓ Ｉｎｃ．、ＮｅｗｂｕｒｙＰｏｒｔ、ＭＡ、ＵＳＡ）、及び１−（４−（４，７−ジクロロ−６−（２−フルオロ−６−ヒドロキシフェニル）フタラジン−１−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン（中間体Ｉ、２２ｍｇ、０．０４９ｍｍｏｌ）の混合物を密封バイアルに入れて６０℃で１６時間撹拌した。反応混合物を濃縮し、残渣をクロマトグラフィー（シリカゲル、ＥｔＯＡｃ０〜１００％含有ヘプタン）で精製し、１−（４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−（（１Ｒ）−１−フェニルエチル）−１−フタラジニル）−１−ピペラジニル）−２−プロペン−１−オンと、１−（４−（７−クロロ−６−（２−フルオロ−６−ヒドロキシフェニル）−４−（（１Ｓ）−１−フェニルエチル）−１−フタラジニル）−１−ピペラジニル）−２−プロペン−１−オンとの混合物が得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、メタノール−ｄ_４） δ ８．２７ （１ Ｈ、ｓ） ８．１５ （０．３３ Ｈ、ｓ） ８．１０ （０．６７ Ｈ、ｓ） ７．１９ − ７．３１ （５ Ｈ、ｍ） ７．１０ − ７．１６ （１ Ｈ、ｍ） ６．８６ （１ Ｈ、ｄｄ、Ｊ ＝ １６．７３、１０．６６ Ｈｚ） ６．６２ − ６．７８ （２ Ｈ、ｍ） ６．２７ （１ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１．９６ Ｈｚ） ５．８０ （１ Ｈ、ｄｄ、Ｊ ＝ １０．６６、１．８６ Ｈｚ） ４．９４ − ５．０１ （１ Ｈ、ｍ） ３．９３ − ４．０３ （４ Ｈ、ｍ） ３．４９ − ３．６０ （４ Ｈ、ｍ） １．８１ （３ Ｈ、ｄ、Ｊ ＝ ７．０４ Ｈｚ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５１７．１。 Example 28
1- (4- (7-Chloro-6- (2-fluoro-6-hydroxyphenyl) -4-((1R) -1-phenylethyl) -1-phthalazinyl) -1-piperazinyl) -2-propen- 1-one and 1- (4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4-((1S) -1-phenylethyl) -1-phthalazinyl) -1-piperazinyl)- 2-Propen-1-on

α-Methylbenzylzinc bromide (0.5 M THF solution, 492 μl, 0.246 mmol), tetrakis (triphenylphosphine) palladium (5.68 mg, 4.92 μmol, Strem Chemicals Inc., NewburyPort, MA, USA), and 1 -(4- (4,7-dichloro-6- (2-fluoro-6-hydroxyphenyl) phthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one (intermediate I, 22 mg) , 0.049 mmol) was placed in a sealed vial and stirred at 60 ° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica, EtOAc 0-100% Heptane) 1- (4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) -4- ( (1R) -1-phenylethyl) -1-phthalazinyl) -1-piperazinyl) -2-propen-1-one and 1-(4- (7-chloro-6- (2-fluoro-6-hydroxyphenyl) ) -4-((1S) -1-phenylethyl) -1-phthalazinyl) -1-piperazinyl) -2-propen-1-one was obtained. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.27 (1 H, s) 8.15 (0.33 H, s) 8.10 (0.67 H, s) 7.19-7. 31 (5 H, m) 7.10-7.16 (1 H, m) 6.86 (1 H, dd, J = 16.73, 10.66 Hz) 6.62-6.78 (2 H) , M) 6.27 (1 H, dd, J = 16.82, 1.96 Hz) 5.80 (1 H, dd, J = 10.66, 1.86 Hz) 4.94-5.01 (1 H, m) 3.93 − 4.03 (4 H, m) 3.49 − 3.60 (4 H, m) 1.81 (3 H, d, J = 7.04 Hz). m / z (ESI) M + H: 517.1.

４−フルオロベンジル亜鉛クロリド（０．５Ｍ ＴＨＦ溶液、０．０８９ｍＬ、０．０４４ｍｍｏｌ）をアルゴン雰囲気下、１−（４−（４，７−ジクロロ−６−（２−フルオロ−６−ヒドロキシフェニル）フタラジン−１−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン（中間体Ｉ、１８ｍｇ、０．０４０ｍｍｏｌ）とテトラキス（トリフェニルホスフィン）パラジウム（４．６５ｍｇ、４．０２μｍｏｌ、Ｓｔｒｅｍ Ｃｈｅｍｉｃａｌｓ Ｉｎｃ．、ＮｅｗｂｕｒｙＰｏｒｔ、ＭＡ、ＵＳＡ）との撹拌した混合テトラヒドロフラン溶液（０．１ｍＬ）に密封バイアル内で加えた。反応混合物を室温で２時間撹拌してから、４０℃に３時間加熱した。さらなる４−フルオロベンジル亜鉛クロリド（０．０８９ｍＬ、０．０４４ｍｍｏｌ）を加え、反応混合物を４０℃でさらに１６時間撹拌した。さらなる４−フルオロベンジル亜鉛クロリド（０．０８９ｍＬ、０．０４４ｍｍｏｌ）を加え、反応混合物を６０℃に加熱し、６時間撹拌した。反応混合物を減圧濃縮した。残渣をクロマトグラフィー（シリカゲル、ＥｔＯＡｃ０〜１００％含有ヘプタン）で精製し、１−（４−（７−クロロ−４−（４−フルオロベンジル）−６−（２−フルオロ−６−ヒドロキシフェニル）−１−フタラジニル）−１−ピペラジニル）−２−プロペン−１−オンが得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、メタノール−ｄ_４） δ ８．３２ （１ Ｈ、ｓ） ８．１９ （１ Ｈ、ｓ） ７．２６ − ７．３４ （３ Ｈ、ｍ） ６．９８ （２ Ｈ、ｔ、Ｊ ＝ ８．７１ Ｈｚ） ６．６９ − ６．９１ （３ Ｈ、ｍ） ６．２８ （１ Ｈ、ｄｄ、Ｊ ＝ １６．９２、１．８６ Ｈｚ） ５．８２ （１ Ｈ、ｄｄ、Ｊ ＝ １０．５６、１．７６ Ｈｚ） ４．５４ − ４．６５ （２ Ｈ、ｍ） ３．９９ （４ Ｈ、ｍ） ３．５８ （４ Ｈ、ｍ）。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５２１．２。 Example 29
1- (4- (7-Chloro-4- (4-fluorobenzyl) -6- (2-fluoro-6-hydroxyphenyl) -1-phthalazinyl) -1-piperazinyl) -2-propene-1-one

4-Fluorobenzylzinc chloride (0.5 M THF solution, 0.089 mL, 0.044 mmol) was added to 1- (4- (4,7-dichloro-6- (2-fluoro-6-hydroxyphenyl)) under an argon atmosphere. Phthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one (intermediate I, 18 mg, 0.040 mmol) and tetrakis (triphenylphosphine) palladium (4.65 mg, 4.02 μmol, Strem) It was added in a sealed vial to a stirred mixed tetrahydrofuran solution (0.1 mL) with Chemicals Inc., NewburyPort, MA, USA). The reaction mixture was stirred at room temperature for 2 hours and then heated to 40 ° C. for 3 hours. Further 4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added and the reaction mixture was stirred at 40 ° C. for an additional 16 hours. Further 4-fluorobenzylzinc chloride (0.089 mL, 0.044 mmol) was added and the reaction mixture was heated to 60 ° C. and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing EtOAc 0 to 100%) and 1-(4- (7-chloro-4- (4-fluorobenzyl) -6- (2-fluoro-6-hydroxyphenyl)-)-. 1-phthalazinyl) -1-piperazinyl) -2-propen-1-one was obtained. ^{1 1} H NMR (400 MHz, methanol-d ₄ ) δ 8.32 (1 H, s) 8.19 (1 H, s) 7.26-7.34 (3 H, m) 6.98 (2 H) , T, J = 8.71 Hz) 6.69-6.91 (3 H, m) 6.28 (1 H, dd, J = 16.92, 1.86 Hz) 5.82 (1 H, dd, J = 10.56, 1.76 Hz) 4.54-4.65 (2 H, m) 3.99 (4 H, m) 3.58 (4 H, m). m / z (ESI) M + H: 521.2.

ステップ１：１，４，６，７−テトラクロロフタラジン（中間体Ｌ）。
ピリジン（４３１μｌ、５．２８ｍｍｏｌ）を、６，７−ジクロロ−２，３−ジヒドロフタラジン−１，４−ジオン（中間体Ｇ、６１０ｍｇ、２．６４ｍｍｏｌ）の撹拌した混合オキシ塩化リン溶液（２．４ｍＬ、２６．４ｍｍｏｌ）に加えた。反応混合物を１００℃に２時間加熱し、その後、冷却し、約１０℃で急速に撹拌された水（７５ｍＬ）にゆっくりと注いだ。得られた懸濁液をろ過し、固体を水で洗浄し、１，４，６，７−テトラクロロフタラジンが得られた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ８．４３ （２ Ｈ、ｓ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ２６６．９。 Examples 30 and 31
2- (1- (4-Acryloyl-1-piperazinyl) -7-chloro-4-phenyl-6-phthalazinyl) -3-fluorophenol (Example 30) and 2- (4- (4-Acryloyl-1-) Piperazinyl) -7-chloro-1-phenyl-6-phthalazinyl) -3-fluorophenol (Example 31)

Step 1: 1,4,6,7-Tetrachlorophthalazine (Intermediate L).
Stirred mixed phosphorus oxychloride solution (2) of pyridine (431 μl, 5.28 mmol) with 6,7-dichloro-2,3-dihydrophthalazine-1,4-dione (Intermediate G, 610 mg, 2.64 mmol). .4 mL, 26.4 mmol). The reaction mixture was heated to 100 ° C. for 2 hours, then cooled and slowly poured into rapidly stirred water (75 mL) at about 10 ° C. The resulting suspension was filtered and the solid was washed with water to give 1,4,6,7-tetrachlorophthalazine. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.43 (2 H, s). m / z (ESI) M + H: 266.9.

Step 2: 4- (4,6,7-trichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl (intermediate M).
1-Boc-piperazine (340 mg, 1.824 mmol) with 1,4,6,7-tetrachlorophthalazine (intermediate L, 543 mg, 2.027 mmol) and triethylamine (0.846 mL, 6.08 mmol). It was added to the stirred mixed dichloromethane solution (8 mL). The reaction mixture was stirred at room temperature for 2 days. An additional 1-boc-piperazine (340 mg, 1.824 mmol) was added and the reaction mixture was stirred at room temperature for an additional 23 hours. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with DCM (30 mL). The organic layer was separated, washed with brine (20 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0% to 50% EtOAc) to give tert-butyl 4- (4,6,7-trichlorophthalazine-1-yl) piperazine-1-carboxylate. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.35 (1 H, s) 8.12 (1 H, s) 3.68-3.75 (4 H, m) 3.45-3.52 (4 H, m) 1.51 (9 H, s). m / z (ESI) M + H: 417.0.

Step 3: tert-butyl 4- (6,7-dichloro-4-phenylphthalazine-1-yl) piperazine-1-carboxylate.
4- (4,6,7-trichlorophthalazine-1-yl) piperazin-1-carboxylate tert-butyl (intermediate M, 95 mg, 0.227 mmol), tetrakis (triphenylphosphine) palladium (26.3 mg,) 0.023 mmol, Strem Chemicals Inc., NewburyPort, MA, USA), phenylboronic acid (27.7 mg, 0.227 mmol), and sodium carbonate (2M aqueous solution, 0.341 mL, 0.682 mmol) are sealed under an argon atmosphere. It was mixed with 1,4-dioxane (1 mL) in a vial. The reaction mixture was stirred at 40 ° C. for 24 hours. Further tetrakis (triphenylphosphine) palladium (26.3 mg, 0.023 mmol) and phenylboronic acid (13.5 mg, 0.113 mmol) were added and the reaction mixture was stirred at 40 ° C. for an additional 24 hours. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with EtOAc (25 mL). The organic layer was separated, washed with brine (20 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptan containing 100% EtOAc 0-100%) to give tert-butyl 4- (6,7-dichloro-4-phenylphthalazine-1-yl) piperazine-1-carboxylate. .. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.13 (1 H, s) 8.07 (1 H, s) 7.62-7.67 (2 H, m) 7.50-7.55 (3 H, m) 3.65-3.74 (4 H, m) 3.44-3.53 (4 H, m) 1.47 (9 H, s). m / z (ESI) M + H: 459.1.

Step 4: 6,7-Dichloro-1-phenyl-4- (piperazine-1-yl) phthalazine.
4- (6,7-Dichloro-4-phenylphthalazine-1-yl) piperazine-1-carboxylate tert-butyl (68 mg, 0.148 mmol) is added to trifluoroacetic acid (1 mL, 13.46 mmol) at room temperature. Was stirred for 20 minutes. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted twice with DCM (25 mL). The organic layer was separated, filtered and dried over MgSO _4, concentrated under reduced pressure, the crude 6,7-dichloro-1-phenyl-4- (piperazin-1-yl) phthalazine are obtained, directly next step it Used in. m / z (ESI) M + H: 359.0.

Step 5: 1- (4- (6,7-dichloro-4-phenylphthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one.
Acryloyl chloride (0.013 mL, 0.162 mmol), 6,7-dichloro-1-phenyl-4- (piperazine-1-yl) phthalazine (53 mg, 0.148 mmol) and triethylamine (0.062 mL, 0.443 mmol) ) And the mixed dichloromethane solution (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (15 mL) and extracted with DCM (20 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 100% EtOAc) and 1- (4- (6,7-dichloro-4-phenylphthalazine-1-yl) piperazine-1-yl) propa-2- En-1-on was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.20 (1 H, s) 8.14 (1 H, s) 7.66-7.75 (2 H, m) 7.54-7.62 (3 H, m) 6.66 (1 H, dd, J = 16.63, 10.37 Hz) 6.37 (1 H, dd, J = 16.82, 1.96 Hz) 5.78 ( 1 H, dd, J = 10.56, 1.96 Hz) 3.85-4.04 (1 H, m) 3.53-3.72 (1 H, m). m / z (ESI) M + H: 431.2.

Step 6: 2- (1- (4-Acryloyl-1-piperazinyl) -7-chloro-4-phenyl-6-phthalazinyl) -3-fluorophenol and 2- (4- (4-acryloyl-1-piperazinyl)) -7-Chloro-1-phenyl-6-phthalazinyl) -3-fluorophenol.
1- (4- (6,7-dichloro-4-phenylphthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one (43 mg, 0.104 mmol), 2-fluoro-6 -Hydroxyphenylboronic acid (17.84 mg, 0.114 mmol, Combi-Blocks Inc., San Diego, CA, USA), SPhos Pd G3 (9.00 mg, 10.40 μmol), and sodium carbonate (2M aqueous solution, 0. 156 mL, 0.312 mmol) was mixed with 1,2-dimethoxyethane (0.5 mL) in a sealed vial under an argon atmosphere. The reaction mixture was stirred at 60 ° C. for 3 hours. Further addition of 2-fluoro-6-hydroxyphenylboronic acid (8.92 mg, 0.057 mmol, Combi-Blocks Inc., San Diego, CA, USA) and SPhos Pd G3 (9.00 mg, 10.40 μmol) was added and the reaction was carried out. The mixture was stirred at 60 ° C. for an additional 2 hours. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (15 mL) and extracted with EtOAc (20 mL). The organic layer was separated, washed with brine (10 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing EtOAc to 100%) to give a mixture of the two positional isomer products. Separation by reverse phase preparative chromatography (XBridge Prep C185 5 μm OBD, 150 × 30 mm; (0.1% TFA-containing water) 35-55% (0.1% TFA-containing acetonitrile); flow rate = 30 mL / min). A positional isomer product was obtained. Fractions containing individual positional isomers were neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with DCM, and the organic extract was concentrated under reduced pressure. The separated positional isomers were further purified individually by column chromatography (silica gel, heptan containing 0 to 100% EtOAc). The first positional isomer eluted from reverse phase preparative chromatography is 2- (1- (4-acryloyl-1-piperazinyl) -7-chloro-4-phenyl-6-phthalazinyl) -3-fluorophenol ( It was Example 30). ¹ H NMR (400 MHz, chloroform-d) δ 8.21 (1 H, s) 8.06 (1 H, s) 7.62-7.69 (2 H, m) 7.45-7.51 (3 H, m) 7.24-7.32 (1 H, m) 6.81-6.90 (1 H, m) 6.75 (1 H, t, J = 8.41 Hz) 6. 65 (1 H, dd, J = 16.82, 10.56 Hz) 6.38 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd, J = 10) .56, 1.76 Hz) 3.86-4.02 (4 H, m) 3.57-3.76 (4 H, m). m / z (ESI) M + H: 489.0. The second positional isomer eluted from the reversed-phase column was 2- (4- (4-acryloyl-1-piperazinyl) -7-chloro-1-phenyl-6-phthalazinyl) -3-fluorophenol (Example 31). )Met. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.15 (1 H, s) 8.12 (1 H, s) 7.68-7.73 (2 H, m) 7.53-7.58 (3 H, m) 7.30 (1 H, br td, J = 8.22, 6.65 Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.78 (1 H, m) t, J = 8.61 Hz) 6.57 (1 H, dd, J = 16.82, 10.56 Hz) 6.28 (1 H, dd, J = 16.73, 1.66 Hz) 5 .71 (1 H, dd, J = 10.56, 1.56 Hz) 3.78-3.89 (4 H, m) 3.51-3.73 (4 H, m). m / z (ESI) M + H: 489.1.

実施例３２及び３３を、実施例３０及び３１と同様の方法で調製した。ただし、ステップ３を以下のとおり変更した。 Examples 32 and 33
2- (1- (4-Acryloyl-1-piperazinyl) -7-chloro-4-methoxy-6-phthalazinyl) -3-fluorophenol (Example 32) and 2- (4- (4-Acryloyl-1-) Piperazinyl) -7-chloro-1-methoxy-6-phthalazinyl) -3-fluorophenol (Example 33)

Examples 32 and 33 were prepared in the same manner as in Examples 30 and 31. However, step 3 was changed as follows.

Step 3: tert-butyl 4- (6,7-dichloro-4-methoxyphthalazine-1-yl) piperazine-1-carboxylate.
4- (4,6,7-trichlorophthalazine-1-yl) piperazine-1-carboxylate tert-butyl (Intermediate M, 198 mg, 0.474 mmol) and sodium methoxide (25% methanol solution, 2 mL, 8) .75 mmol) was mixed in a sealed vial. The reaction mixture was stirred at 60 ° C. for 2 hours. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (25 mL) and extracted with EtOAc (25 mL). The organic layer was separated, washed with brine (20 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0-50% EtOAc) to give tert-butyl 4- (6,7-dichloro-4-methoxyphthalazine-1-yl) piperazine-1-carboxylate. .. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.29 (1 H, s) 8.08 (1 H, s) 4.22 (3 H, s) 3.68-3.73 (4 H, m) 3.33-3.38 (4 H, m) 1.51 (9 H, s). m / z (ESI) M + H: 413.1.

From step 6: First elution position isomer: 2- (1- (4-acryloyl-1-piperazinyl) -7-chloro-4-methoxy-6-phthalazinyl) -3-fluorophenol (Example 32)
^{1 1} H NMR (400 MHz, chloroform-d) δ 8.23 (1 H, s) 8.11 (1 H, s) 7.32 (1 H, td, J = 8.31, 6.46 Hz) 6.88 (1 H, d, J = 8.22 Hz) 6.77-6.83 (1 H, m) 6.65 (1 H, dd, J = 16.82, 10.56 Hz) 6 .37 (1 H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd, J = 10.47, 1.86 Hz) 4.18 (3 H, s) 3. 79-4.05 (4 H, m) 3.34-3.54 (4 H, m). m / z (ESI) M + H: 443.1.

Second elution position isomer: 2- (4- (4-acryloyl-1-piperazinyl) -7-chloro-1-methoxy-6-phthalazinyl) -3-fluorophenol (Example 33)
^{1 1} H NMR (400 MHz, chloroform-d) δ 8.32 (1 H, s) 8.01 (1 H, s) 7.32 (1 H, td, J = 8.27, 6.55 Hz) 6.89 (1 H, d, J = 8.22 Hz) 6.77-6.83 (1 H, m) 6.60 (1 H, dd, J = 17.02, 10.56 Hz) 6 .30 (1 H, dd, J = 16.82, 1.76 Hz) 5.75 (1 H, dd, J = 10.56, 1.76 Hz) 4.22 (3 H, s) 3. 67-3.98 (4 H, m) 3.25-3.55 (4 H, m). m / z (ESI) M + H: 443.1.

実施例３４を、実施例３０及び３１と同様の方法で調製した。ただし、ステップ６を省略し、ステップ２及び３を以下のとおり変更した。 Example 34:
1- (4-Acryloyl-1-piperazinyl) -4-benzyl-6,7-dichlorophthalazine

Example 34 was prepared in the same manner as in Examples 30 and 31. However, step 6 was omitted and steps 2 and 3 were changed as follows.

Steps 2 and 3: tert-butyl 4- (4-benzyl-6,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate.
Benzyl zinc bromide (0.5 M THF solution, 1.926 mL, 0.963 mmol) under an argon atmosphere, 1,4,6,7-tetrachlorophthalazine (intermediate L, 258 mg, 0.963 mmol) and tetrakis (tri). Phenylphosphine) was added to a sealed vial containing palladium (111 mg, 0.096 mmol, Strem Chemicals Inc., NewburyPort, MA, USA). The reaction mixture was stirred at room temperature for 16 hours. 1-Boc-piperazine (1.79 g, 9.63 mmol) was added and the reaction mixture was stirred at 60 ° C. for 5 hours. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (40 mL) and extracted with EtOAc (50 mL). The organic layer was separated, washed with brine (40 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, heptane containing 0-50% EtOAc) to give tert-butyl 4- (4-benzyl-6,7-dichlorophthalazine-1-yl) piperazine-1-carboxylate. .. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.11 (1 H, s) 8.10 (1 H, s) 7.27-7.35 (4 H, m) 7.20-7.25 (1 H, m) 4.59 (2 H, s) 3.69-3.74 (4 H, m) 3.44-3.49 (4 H, m) 1.52 (9 H, s) .. m / z (ESI) M + H: 473.1. m / z (ESI) M + H: 473.1.

From step 5: 1- (4-acryloyl-1-piperazinyl) -4-benzyl-6,7-dichlorophthalazine. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.13 (1 H, s) 8.12 (1 H, s) 7.28-7.36 (4 H, m) 7.20-7. 26 (1 H, m) 6.65 (1 H, dd, J = 16.82, 10.56 Hz) 6.37 (1 H, dd, J = 16.82, 1.57 Hz) 5.78 (1 H, dd, J = 10.56, 1.56 Hz) 4.61 (2 H, s) 3.83-4.01 (4 H, m) 3.48-3.62 (4 H, s) m). m / z (ESI) M + H: 427.1.

１−（４−（４−ベンジル−６，７−ジクロロフタラジン−１−イル）ピペラジン−１−イル）プロパ−２−エン−１−オン。（実施例３４、３５ｍｇ、０．０８２ｍｍｏｌ）、２−フルオロ−６−ヒドロキシフェニルボロン酸（１２．７７ｍｇ、０．０８２ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ Ｉｎｃ．、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）、ＳＰｈｏｓ Ｐｄ Ｇ３（７．０９ｍｇ、８．１９μｍｏｌ）、及び炭酸ナトリウム（２Ｍ水溶液、０．１２３ｍＬ、０．２４６ｍｍｏｌ）をアルゴン雰囲気下、密封バイアル内で１，２−ジメトキシエタン（０．３ｍＬ）に混合した。反応混合物を６０℃で１時間撹拌した。反応混合物の反応を飽和炭酸水素ナトリウム水溶液（１５ｍＬ）で停止させ、ＥｔＯＡｃ（２０ｍＬ）で抽出した。有機層を分離し、食塩水（１０ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥させ、ろ過して減圧濃縮した。残渣をクロマトグラフィー（シリカゲル、ＥｔＯＡｃ０〜１００％含有ヘプタン）で精製し、２つの位置異性体生成物の混合物が得られた。逆相分取クロマトグラフィー（ＸＢｒｉｄｇｅ Ｐｒｅｐ Ｃ１８ ５μｍ ＯＢＤ、１５０×３０ｍｍ；（０．１％ＴＦＡ含有水）２０〜９０％含有（０．１％ＴＦＡ含有アセトニトリル）；流量＝３０ｍＬ／分）で、部分的に分離した位置異性体生成物が得られた。位置異性体を含有する画分を飽和炭酸水素ナトリウム水溶液で中和してＤＣＭで抽出し、有機抽出物を減圧濃縮した。逆相分取クロマトグラフィーで第１に溶出した位置異性体は２−（１−（４−アクリロイル−１−ピペラジニル）−４−ベンジル−７−クロロ−６−フタラジニル）−３−フルオロフェノール（実施例３５）であり、約３６％の第２溶出位置異性体を含有していた。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ８．１３ （１ Ｈ、ｓ） ８．１１ （１ Ｈ、ｓ） ７．１２ − ７．３７ （６ Ｈ、ｍ） ６．９１ （１ Ｈ、ｄ、Ｊ ＝ ８．２２ Ｈｚ） ６．７７ （１ Ｈ、ｔ、Ｊ ＝ ８．６１ Ｈｚ） ６．６４ （１ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１０．５６ Ｈｚ） ６．３７ （１ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１．７６ Ｈｚ） ５．７９ （１ Ｈ、ｄｄ、Ｊ ＝ １０．５６、１．９６ Ｈｚ） ４．５５ （２ Ｈ、ｓ） ３．３４ − ４．０１ （８ Ｈ、ｍ）。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５０３．１。第２に溶出した位置異性体は２−（４−（４−アクリロイル−１−ピペラジニル）−１−ベンジル−７−クロロ−６−フタラジニル）−３−フルオロフェノール（実施例３６）であった。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ８．１２ （１ Ｈ、ｓ） ８．０５ （１ Ｈ、ｓ） ７．２６ − ７．３６ （５ Ｈ、ｍ） ７．１９ − ７．２４ （１ Ｈ、ｍ） ６．９３ （１ Ｈ、ｄ、Ｊ ＝ ８．４１ Ｈｚ） ６．７６ （１ Ｈ、ｔ、Ｊ ＝ ８．３１ Ｈｚ） ６．５８ （１ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１０．７６ Ｈｚ） ６．２８ （１ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１．７６ Ｈｚ） ５．７５ （１ Ｈ、ｄｄ、Ｊ ＝ １０．５６、１．７６ Ｈｚ） ４．５４ （２ Ｈ、ｓ） ３．３２ − ３．９３ （８ Ｈ、ｍ）。ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５０３．１。 Examples 35 and 36:
2- (1- (4-Acryloyl-1-piperazinyl) -4-benzyl-7-chloro-6-phthalazinyl) -3-fluorophenol (Example 35) and 2- (4- (4-Acryloyl-1-) Piperazinyl) -1-benzyl-7-chloro-6-phthalazinyl) -3-fluorophenol (Example 36)

1- (4- (4-Benzyl-6,7-dichlorophthalazine-1-yl) piperazine-1-yl) propa-2-ene-1-one. (Example 34, 35 mg, 0.082 mmol), 2-fluoro-6-hydroxyphenylboronic acid (12.77 mg, 0.082 mmol, Combi-Blocks Inc., San Diego, CA, USA), SPhos Pd G3 (7). .09 mg, 8.19 μmol) and sodium carbonate (2M aqueous solution, 0.123 mL, 0.246 mmol) were mixed with 1,2-dimethoxyethane (0.3 mL) in a sealed vial under an argon atmosphere. The reaction mixture was stirred at 60 ° C. for 1 hour. The reaction of the reaction mixture was stopped with saturated aqueous sodium hydrogen carbonate solution (15 mL) and extracted with EtOAc (20 mL). The organic layer was separated, washed with brine (10 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, Heptane containing EtOAc to 100%) to give a mixture of the two positional isomer products. In reverse phase preparative chromatography (XBride Prep C185 5 μm OBD, 150 × 30 mm; (0.1% TFA-containing water) 20-90% (0.1% TFA-containing acetonitrile); flow rate = 30 mL / min) A segregated position isomer product was obtained. The fraction containing the positional isomer was neutralized with saturated aqueous sodium hydrogen carbonate solution, extracted with DCM, and the organic extract was concentrated under reduced pressure. The first position isomer eluted by reverse phase preparative chromatography was 2- (1- (4-acryloyl-1-piperazinyl) -4-benzyl-7-chloro-6-phthalazinyl) -3-fluorophenol (implemented). Example 35), which contained about 36% of the second elution position isomer. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.13 (1 H, s) 8.11 (1 H, s) 7.12-7.37 (6 H, m) 6.91 (1 H, 1 H, s) d, J = 8.22 Hz) 6.77 (1 H, t, J = 8.61 Hz) 6.64 (1 H, dd, J = 16.82, 10.56 Hz) 6.37 (1) H, dd, J = 16.82, 1.76 Hz) 5.79 (1 H, dd, J = 10.56, 1.96 Hz) 4.55 (2 H, s) 3.34-4. 01 (8 H, m). m / z (ESI) M + H: 503.1. The second eluted positional isomer was 2- (4- (4-acryloyl-1-piperazinyl) -1-benzyl-7-chloro-6-phthalazinyl) -3-fluorophenol (Example 36). ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.12 (1 H, s) 8.05 (1 H, s) 7.26-7.36 (5 H, m) 7.19-7.24 (1 H, m) 6.93 (1 H, d, J = 8.41 Hz) 6.76 (1 H, t, J = 8.31 Hz) 6.58 (1 H, dd, J = 16) .82, 10.76 Hz) 6.28 (1 H, dd, J = 16.82, 1.76 Hz) 5.75 (1 H, dd, J = 10.56, 1.76 Hz) 4. 54 (2 H, s) 3.32-3.93 (8 H, m). m / z (ESI) M + H: 503.1.

実施例３７を、実施例３５及び３６と同様の方法で調製し、その際、２−フルオロ−６−ヒドロキシフェニルボロン酸の代わりに５−メチル−１ｈ−インダゾール−４−イルボロン酸（Ｃｏｍｂｉ−Ｂｌｏｃｋｓ Ｉｎｃ．、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）を用いた。この実施形態では、２つの位置異性体生成物は分離していなかった。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ８．２３ （０．６ Ｈ、ｓ） ８．２２ （０．４ Ｈ、ｓ） ８．０２ （０．４ Ｈ、ｓ） ８．００ （０．６ Ｈ、ｓ） ７．１９ − ７．５７ （８ Ｈ、ｍ） ６．６８ （０．４ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１０．５６ Ｈｚ） ６．６０ （０．６ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１０．５６ Ｈｚ） ６．３８ （０．４ Ｈ、ｄｄ、Ｊ ＝ １６．６３、１．７６ Ｈｚ） ６．３２ （０．６ Ｈ、ｄｄ、Ｊ ＝ １６．８２、１．７６ Ｈｚ） ５．７９ （０．４ Ｈ、ｄｄ、Ｊ ＝ １０．５６、１．７６ Ｈｚ） ５．７３ （０．６ Ｈ、ｄｄ、Ｊ ＝ １０．５６、１．７６ Ｈｚ） ４．６７ （１．２ Ｈ、ｓ） ４．６０ （０．８ Ｈ、ｓ） ３．７４ − ４．０６ （４ Ｈ、ｍ） ３．４６ − ３．７０ （４ Ｈ、ｍ） ２．２１ （１．８ Ｈ、ｓ） ２．０６ （１．２ Ｈ、ｓ）。 ｍ／ｚ （ＥＳＩ） Ｍ＋Ｈ： ５２３。 Example 37
1- (4-Acryloyl-1-piperazinyl) -4-benzyl-6-chloro-7- (5-methyl-1H-indazole-4-yl) phthalazine and 1- (4-acryloyl-1-piperazinyl) -4 -Benzyl-7-chloro-6- (5-methyl-1H-indazole-4-yl) phthalazine

Example 37 was prepared in a similar manner to Examples 35 and 36, in which 5-methyl-1h-indazole-4-ylboronic acid (Combi-Blocks) was used instead of 2-fluoro-6-hydroxyphenylboronic acid. Inc., San Diego, CA, USA) was used. In this embodiment, the two positional isomer products were not separated. ¹ H NMR (400 MHz, chloroform-d) δ 8.23 (0.6 H, s) 8.22 (0.4 H, s) 8.02 (0.4 H, s) 8.00 (0) .6 H, s) 7.19-7.57 (8 H, m) 6.68 (0.4 H, dd, J = 16.82, 10.56 Hz) 6.60 (0.6 H, 0.6 H, s) dd, J = 16.82, 10.56 Hz) 6.38 (0.4 H, dd, J = 16.63, 1.76 Hz) 6.32 (0.6 H, dd, J = 16. 82, 1.76 Hz) 5.79 (0.4 H, dd, J = 10.56, 1.76 Hz) 5.73 (0.6 H, dd, J = 10.56, 1.76 Hz) ) 4.67 (1.2 H, s) 4.60 (0.8 H, s) 3.74-4.06 (4 H, m) 3.46-3.70 (4 H, m) 2 .21 (1.8 H, s) 2.06 (1.2 H, s). m / z (ESI) M + H: 523.

方法８、ステップ１〜４に試薬として２，５，６−トリクロロニコチン酸（ステップ１）、アミノメチルシクロプロパン（ステップ２）、２−フルオロ−６−ヒドロキシフェニルボロン酸（ステップ４、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ Ｉｎｃ．、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）、及び炭酸ナトリウム（ステップ４）を使用して、実施例３８の出発物質を調製した。 Example 38
6-Chloro-1- (cyclopropylmethyl) -7- (2-fluoro-6-hydroxyphenyl) -4- (4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine- 2 (1H) -on

Method 8, Steps 1 to 4 as reagents 2,5,6-trichloronicotinic acid (step 1), aminomethylcyclopropane (step 2), 2-fluoro-6-hydroxyphenylboronic acid (step 4, Combi-Blocks). Inc., San Diego, CA, USA), and sodium carbonate (step 4) were used to prepare the starting material of Example 38.

Step 1: 7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-1- (cyclopropylmethyl) pyrido [2,3-d] pyrimidine-2,4 ( 1H, 3H) -Zeon.
tert-Butylchlorodiphenylsilane (0.036 mL, 0.139 mmol), 6-chloro-1- (cyclopropylmethyl) -7- (2-fluoro-6-hydroxyphenyl) pyrido [2,3-d] pyrimidine It was added to a stirred mixed acetonitrile solution (0.5 mL) of −2,4 (1H, 3H) -dione (42 mg, 0.116 mmol) and triethylamine (0.065 mL, 0.464 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous _NH 4 Cl (25 mL), and extracted with EtOAc (30 mL). The organic layer is separated, washed with brine (25 mL), dried over sulfonyl ₄ , filtered and concentrated under reduced pressure, crude 7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl). -6-Chloro-1- (cyclopropylmethyl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -dione was obtained and used directly in the next step. m / z (ESI) M + H: 599.8.

Step 2: 4- (4-Acryloylpiperazin-1-yl) -7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-1- (cyclopropylmethyl) pyridod [2,3-d] Pyrimidine-2 (1H) -on.
Phosphoryl oxychloride (0.087 mL, 0.933 mmol) was added to crude 7-(2-((tert-butyldiphenylsilyl) oxy) -6-fluorophenyl) -6-chloro-1- (cyclopropylmethyl) pyridode [ 2,3-d] pyrimidin-2,4 (1H, 3H) -dione (70 mg, 0.117 mmol), triethylamine (0.295 mL, 2.099 mmol), and 1H-benzo [d] [1,2,3 ] Triazole (167 mg, 1.400 mmol) was added to a stirred solution of acetonitrile (2 mL). The reaction mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in 1,2-dichloroethane (2 mL) and triethylamine (0.295 mL, 2.099 mmol) and 1- (piperazine-1-yl) propa-2-ene-1-one (32.7 mg,). 0.233 mmol, eNovation Chemicals LLC, Bridgewater, NJ, USA) was added. The reaction mixture was stirred at room temperature for 16 hours. Additional triethylamine (0.148 mL, 1.050 mmol) and 1- (piperazine-1-yl) propa-2-ene-1-one (32.7 mg, 0.233 mmol, eNovation Chemicals LLC, Bridgewater, NJ, USA) In addition, the reaction mixture was stirred at room temperature for 1 hour, then heated to 60 ° C. and stirred for 4 hours. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution (40 mL) and extracted with DCM (50 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The resulting residue was retaken in 1,2-dichloroethane (2 mL) and triethylamine (0.295 mL, 2.099 mmol) and 1- (piperazine-1-yl) propa-2-ene-1-one (32.7 mg). , 0.233 mmol, eNovation Chemicals LLC, Bridgewater, NJ, USA). The reaction mixture was stirred at 60 ° C. for 6 hours. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution (40 mL) and extracted with DCM (50 mL). The organic layer was separated, dried over butadiene ₄ , filtered and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, (EtOAc / EtOH 3: 1) 0-100% heptan) and 4- (4-acryloyl piperazin-1-yl) -7-(2-((tert-butyldiphenyl)). Cyril) oxy) -6-fluorophenyl) -6-chloro-1- (cyclopropylmethyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained, which could be followed without further purification. Used in steps. m / z (ESI) M + H: 721.8.

Step 3: 4- (4-Acryloylpiperazin-1-yl) -6-chloro-1- (cyclopropylmethyl) -7- (2-fluoro-6-hydroxyphenyl) pyrido [2,3-d] pyrimidine- 2 (1H) -on.
Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.025 mL, 0.025 mmol), 4- (4-acryloylpiperazin-1-yl) -7-(2-((tert-butyldiphenylsilyl) oxy) A stirred mixed tetrahydrofuran solution of -6-fluorophenyl) -6-chloro-1- (cyclopropylmethyl) pyrido [2,3-d] piperazine-2 (1H) -one (6 mg, 8.31 μmol) (0. 2 mL) was added. The reaction mixture was stirred at room temperature for 20 minutes and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel, (EtOAc / EtOH 3: 1) 0-100% heptan) and 6-chloro-1- (cyclopropylmethyl) -7- (2-fluoro-6-hydroxyphenyl). -4- (4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ 8.04 (1 H, s) 7.26-7.33 (1 H, m) 6.82 (1 H, d, J = 8.29 Hz) 6.71 (1 H, t, J = 8.91 Hz) 6.51 (1 H, dd, J = 16.79, 10.57 Hz) 6.30 (1 H, dd, J = 16.79 , 1.45 Hz) 5.72 (1 H, dd, J = 10.47, 1.55 Hz) 4.15 (2 H, br d, J = 6.43 Hz) 3.69-3.90 (8 H, m) 1.14-1.27 (4 H, m) 0.73 − 0.88 (1 H, m). m / z (ESI) M + H: 483.8.

ステップ１：２，５，６−トリクロロニコチンアミド（中間体Ｐ）。
１，１′−カルボニルジイミダゾール（４０ｇ、２４７ｍｍｏｌ）を２，５，６−トリクロロニコチン酸（５０．７ｇ、２２４ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）のＴＨＦ溶液（４００ｍＬ）に少しずつ加え、添加の合間のガス発生が止まるようにした。得られた混合物を５分間撹拌し、その後、掃除機で脱気し、窒素でフラッシュした（２回）。得られた混合物を５０℃に６０分間加熱し、その後、トルエン（１００ｍＬ）で希釈し、体積が半分になるまで濃縮した。得られた混合物を０℃に冷却し、水酸化アンモニウム（６０ｍＬ、４３７ｍｍｏｌ）をシリンジでゆっくりと加えた。反応物を１０分間室温で撹拌し、ＥｔＯＡｃ（２００ｍＬ）で希釈し、水で洗浄した（１００ｍＬ、３回）。有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をヘプタン／ＥｔＯＡｃ（９：１）（３００ｍＬ）に懸濁させ、ろ過した。ろ過後の固形物を回収し、残った母液を一部蒸発させて体積を半分にし、０℃に冷却してろ過した。ろ別された２種の固形物を合わせ、２，５，６−トリクロロニコチンアミドを得た。 Example 39
6-Chloro-7- (2-Fluoro-6-Hydroxyphenyl) -1- (2-Methyl-6- (2-Propanil) Phenyl) -4-((2S) -2-Methyl-4- (2-) Propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 2,5,6-trichloronicotinamide (Intermediate P).
Little by little 1,1'-carbonyldiimidazole (40 g, 247 mmol) in THF solution (400 mL) of 2,5,6-trichloronicotinic acid (50.7 g, 224 mmol, Combi-Blocks, San Diego, CA, USA) In addition, gas generation was stopped between additions. The resulting mixture was stirred for 5 minutes, then vacuumed and flushed with nitrogen (twice). The resulting mixture was heated to 50 ° C. for 60 minutes, then diluted with toluene (100 mL) and concentrated to half the volume. The resulting mixture was cooled to 0 ° C. and ammonium hydroxide (60 mL, 437 mmol) was added slowly with a syringe. The reaction was stirred for 10 minutes at room temperature, diluted with EtOAc (200 mL) and washed with water (100 mL, 3 times). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in heptane / EtOAc (9: 1) (300 mL) and filtered. The solid matter after filtration was collected, and the remaining mother liquor was partially evaporated to halve the volume, cooled to 0 ° C., and filtered. The two solids separated by filtration were combined to give 2,5,6-trichloronicotinamide.

Step 2: 2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl) carbamoyl) nicotinamide.
Oxalyl chloride (2M DCM solution, 2.7 mL, 5.4 mmol) was added to a mixed THF solution (30 mL) of 2,5,6-trichloronicotinamide (intermediate P, 1.13 g, 5.0 mmol). The resulting slurry was heated at 65 ° C. for 40 minutes, then the heating was stopped and the reaction was cooled to room temperature. 2-Isopropyl-6-methylaniline (0.80 mL, 5.36 mmol, Enamine, Monmouth Junction, NJ, USA) was added and the reaction was stirred at room temperature for 14 hours. The reaction was concentrated and the residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was suspended in heptane / EtOAc (5: 1) (10 mL) and filtered. The solid matter after filtration was recovered to obtain 2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl) carbamoyl) nicotinamide. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 9.63 (s, 1 H), 9.35 (br s, 1 H), 8.25 (s, 1 H), 7.19-7. 26 (m, 2H), 7.13 (d, J = 7.3 Hz, 1H), 3.14 (quin, J = 6.9 Hz, 1H), 2.29 (s, 3H) ), 1.23 (d, J = 6.8 Hz, 6 H). m / z (ESI, + ve ion): 400.0 (M + H) ⁺ .

Step 3: 6,7-Dichloro-1- (2-isopropyl-6-methylphenyl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
2. KHMDS (1M THF solution, 7.) in a mixed THF solution (20 mL) of 2,5,6-trichloro-N-((2-isopropyl-6-methylphenyl) carbamoyl) nicotinamide (1.45 g, 3.6 mmol). 5 mL, 7.5 mmol) was added. After stirring at room temperature for 30 minutes, the reactants were concentrated to 1/3 volume and the reaction was stopped with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with EtOAc (40 mL). The organic layer was washed with saline (10 mL), dried over anhydrous sodium sulfate and concentrated to concentrate 6,7-dichloro-1- (2-isopropyl-6-methylphenyl) pyrido [2,3-d] pyrimidine-. 2,4 (1H, 3H) -dione was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 364.0 (M + H) ⁺ .

Step 4: 4- (6,7-dichloro-1- (2-isopropyl-6-methylphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3- Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
Crude 6,7-dichloro-1- (2-isopropyl-6-methylphenyl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (3.6 mmol) mixed acetonitrile solution (10 mL) ) Was added DIPEA (1.50 mL, 8.6 mmol), followed by phosphorus oxychloride (0.50 mL, 5.3 mmol). The resulting mixture was heated at 80 ° C. for 1 hour, then cooled to room temperature and concentrated. The residue was dissolved in DMF (15 mL), treated with DIPEA (1.50 mL, 8.6 mmol), then (S) -4-N-Boc-2-methylpiperazine (900 mg, 4.5 mmol, ArkPharm Inc.). Treated with Arlington Heights, IL, USA). The resulting solution was stirred at room temperature for 14 hours and then diluted with EtOAc (30 mL). The mixture was washed with water (10 mL) and brine (10 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 10-50% / heptane) and 4- (6,7-dichloro-1- (2-isopropyl-6-methylphenyl)-. 2-Oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ¹ H NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.45 (s, 1 H), 7.34-7.43 (m, 2 H), 7.23 (d, J = 7.3 Hz) , 1 H), 4.97 (br s, 1 H), 4.34 (br d, J = 13.3 Hz, 1 H), 4.15 (br d, J = 12.0 Hz, 1 H) ), 4.01 (br d, J = 13.7 Hz, 1 H), 3.80 (br s, 1 H), 3.09-3.32 (m, 2 H), 2.49-2 .59 (m, 1H), 1.99 (d, J = 3.7 Hz, 3H), 1.55 (s, 9H), 1.50 (dd, J = 1.7, 6. 6 Hz, 3 H), 1.18 (dd, J = 6.7, 1.8 Hz, 3 H), 1.09 (dd, J = 6.8, 2.3 Hz, 3 H). m / z (ESI, + ve ion): 546.1 (M + H) ⁺ .

Step 5: 4- (6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -2-oxo-1,2-dihydropyride [2,3- d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (6,7-dichloro-1- (2-isopropyl-6-methylphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3 in a round bottom flask -Methylpiperazin-1-carboxylic acid (S) -tert-butyl (8.3 g, 15.19 mmol), potassium acetate (7.50 g, 76 mmol) and [1,1'-bis (diphenylphosphino) ferrocene]- A dichloropalladium (II) dichloromethane complex (0.495 g, 0.606 mmol) was added. 1,4-Dioxane (40 mL) and water (8 mL) were added and the mixture was heated to 90 ° C. (2-Fluoro-6-Hydroxyphenyl) Potassium Trifluoroborate (Intermediate Q, 7.45 g, 34.2 mmol) and additional [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) dichloromethane The complex (0.176 g) was added. The resulting mixture was stirred at room temperature for 2.5 hours, then cooled to room temperature, diluted with EtOAc (200 mL) and washed with water (1 time) and brine (1 time). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 5-40% / heptane) and 4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1-. (2-Isopropyl-6-methylphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl Got ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.68 (br s, 1 H), 8.14 (br s, 1 H), 7.33-7.45 (m, 2 H), 7 .25 (d, J = 6.3 Hz, 2H), 6.64-6.73 (m, 2H), 3.91-5.15 (m, 4H), 3.67 (br s) , 1H), 3.32 (br s, 2H), 2.49-2.76 (m, 1H), 1.95-2.08 (m, 3H), 1.53 (s, 12 H), 1.14-1.29 (m, 3 H), 0.95-1.07 (m, 3 H). ¹⁹ F NMR (377 MHz, chloroform-d) δ ppm -104.56 (br s, 1 F). m / z (ESI, + ve ion): 622.1 (M + H) ⁺ .

Step 6: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-methyl-6- (2-propanil) phenyl) -4-((2S) -2-methyl-4- (2-Propenoyl) -1-piperazinyl) Pyrid [2,3-d] Pyrimidine-2 (1H) -on.
4- (6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidine Add trifluoroacetic acid (1.5 mL, 19.6 mmol) to a DCM solution (10 mL) of -4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl (680 mg, 1.1 mmol). It was. The reaction was stirred for 1.5 hours at room temperature and then concentrated. The residue was partitioned between EtOAc (40 mL) and saturated aqueous sodium hydrogen carbonate solution (15 mL, twice). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in DCM (10 mL) and treated with DIPEA (0.5 mL, 2.9 mmol) and then with acryloyl chloride (0.09 mL, 1.1 mmol). The reaction was stirred for 10 minutes at room temperature, then diluted with EtOAc (30 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 10-60% / heptane) and 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-). Methyl-6- (2-propanyl) phenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H)- Got on. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.07 (s, 1 H), 8.40 (br s, 1 H), 7.17-7.25 (m, 3 H), 7 .06-7.13 (m, 1H), 6.79-6.91 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 8.8 Hz, 1 H), 6.20 (br d, J = 16.8 Hz, 1 H), 5.73-5.78 (m, 1 H), 4.91 (br s, 1H), 4.21-4.46 (m, 2H), 3.95-4.20 (m, 1H), 3.42-3.80 (m, 2H), 3.03- 3.27 (m, 1 H), 2.53-2.63 (m, 1 H), 1.85 (br s, 3 H), 1.32 (br t, J = 5.9 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.91 (br d, J = 6.6 Hz, 3 H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ ppm −115.71 − −115.50 (m, 1 F), -116.16 (br s, 1 F). m / z (ESI, + ve ion): 576.0 (M + H) ⁺ .

（２−フルオロ−６−ヒドロキシフェニル）カリウムトリフルオロボラート（中間体Ｑ）。
フッ化カリウム（４４．７ｇ、７７０ｍｍｏｌ）の水溶液（７５ｍＬ）を、（２−フルオロ−６−ヒドロキシフェニル）ボロン酸（３０ｇ、１９２ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）のアセトニトリル懸濁溶液（７５０ｍＬ）に加えた。混合物を２分間撹拌し、その後、Ｌ−（＋）−酒石酸（７２．２ｇ、４８１ｍｍｏｌ）のＴＨＦ溶液（３７５ｍＬ）を付加漏斗で１０分かけて加えた。混合物を機械的撹拌装置で１時間激しく撹拌し、その後、得られた懸濁液をろ過し、ろ過後の固形物を少量のＴＨＦで洗浄した。固形物を捨て、溶液から固体が析出し始めるまでろ液を部分的に濃縮した。その後、混合物を−２０℃に冷却し、１６時間撹拌した。反応物を徐々に昇温させ、２−プロパノール（２０ｍＬ）を加えた。得られた懸濁液をろ過し、ろ過後の固形物を２−プロパノールで洗浄した。ろ液を再度、部分的に濃縮して懸濁液を形成させ、その後、−２０℃に冷却し、さらに２０分間撹拌した。得られた懸濁液を２−プロパノールで希釈してろ過し、ろ過後の固形物を２−プロパノールで洗浄した。２バッチの固体を合わせ、２−フルオロ−６−ヒドロキシフェニル）カリウムトリフルオロボラートを得た（中間体Ｑ）。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ ８．０７ （ｑ、Ｊ ＝ １４．７ Ｈｚ、１ Ｈ） ６．９３ （ｑ、Ｊ ＝ ７．５ Ｈｚ、１ Ｈ） ６．３０−６．３８ （ｍ、２ Ｈ）。

(2-Fluoro-6-Hydroxyphenyl) Potassium trifluoroborate (Intermediate Q).
An aqueous solution (75 mL) of potassium fluoride (44.7 g, 770 mmol) in an acetonitrile suspension solution of (2-fluoro-6-hydroxyphenyl) boric acid (30 g, 192 mmol, Combi-Blocks, San Diego, CA, USA). Was added to (750 mL). The mixture was stirred for 2 minutes and then a solution of L- (+)-tartaric acid (72.2 g, 481 mmol) in THF (375 mL) was added in an addition funnel over 10 minutes. The mixture was vigorously stirred with a mechanical stirrer for 1 hour, after which the resulting suspension was filtered and the filtered solid was washed with a small amount of THF. The solids were discarded and the filtrate was partially concentrated until solids began to precipitate from the solution. The mixture was then cooled to −20 ° C. and stirred for 16 hours. The reaction was gradually warmed up and 2-propanol (20 mL) was added. The resulting suspension was filtered and the filtered solid was washed with 2-propanol. The filtrate was again partially concentrated to form a suspension, then cooled to −20 ° C. and stirred for an additional 20 minutes. The obtained suspension was diluted with 2-propanol and filtered, and the filtered solid was washed with 2-propanol. Two batches of solids were combined to give 2-fluoro-6-hydroxyphenyl) potassium trifluoroborate (Intermediate Q). ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.07 (q, J = 14.7 Hz, 1 H) 6.93 (q, J = 7.5 Hz, 1 H) 6.30- 6.38 (m, 2H).

ステップ１：２−イソプロピル−４−メチルピリジン−３−アミン（中間体Ｒ）。
３−アミノ−２−ブロモ−４−ピコリン（３６０ｍｇ、１．９ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）のＴＨＦ溶液（４ｍＬ）のスラリーに［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（７９ｍｇ、０．１０ｍｍｏｌ）を加えた。得られたスラリーをアルゴンを用いて２分間脱酸素処理をし、その後、２−プロピル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、５．４０ｍＬ、２．７ｍｍｏｌ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ）を加えた。得られた溶液を６０℃で１７時間加熱した後、加熱を中止し、反応物を室温に冷却した。反応混合物の反応を水（１０ｍＬ）及び１Ｎ ＮａＯＨ溶液（２０ｍＬ）で停止させ、その後、ＥｔＯＡｃで抽出した（２回）。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＭｅＯＨ０〜１５％／ＤＣＭ）で精製し、２−イソプロピル−４−メチルピリジン−３−アミンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ ７．６６ （ｄ、Ｊ ＝ ４．６ Ｈｚ、１ Ｈ）、６．７８ （ｄ、Ｊ ＝ ４．８ Ｈｚ、１ Ｈ）、４．７２ （ｂｒ ｓ、２ Ｈ）、３．１４−３．２５ （ｍ、１ Ｈ）、２．０８ （ｓ、３ Ｈ）、１．１４ （ｄ、Ｊ ＝ ６．８ Ｈｚ、６ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： １５１．１ （Ｍ＋Ｈ）^＋。 Example 40
6-Chloro-7- (2-fluorophenyl) -1- (4-methyl-2- (2-propanil) -3-pyrimidine) -4-((2S) -2-methyl-4- (2-propenoyl) ) -1-Piperadinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 2-Isopropyl-4-methylpyridine-3-amine (Intermediate R).
[1,1'-Bis (diphenylphosphino)] in a slurry of THF solution (4 mL) of 3-amino-2-bromo-4-picoline (360 mg, 1.9 mmol, Combi-Blocks, San Diego, CA, USA). Ferrocene] Dichloropalladium (II) dichloromethane complex (79 mg, 0.10 mmol) was added. The resulting slurry is deoxidized with argon for 2 minutes, followed by 2-propyl zinc bromide (0.5 M THF solution, 5.40 mL, 2.7 mmol, Sigma-Aldrich, St. Louis, MO). added. The resulting solution was heated at 60 ° C. for 17 hours, then the heating was stopped and the reaction was cooled to room temperature. The reaction of the reaction mixture was stopped with water (10 mL) and 1N NaOH solution (20 mL) and then extracted with EtOAc (twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-15% / DCM) to give 2-isopropyl-4-methylpyridine-3-amine. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.66 (d, J = 4.6 Hz, 1 H), 6.78 (d, J = 4.8 Hz, 1 H), 4. 72 (br s, 2 H), 3.14-3.25 (m, 1 H), 2.08 (s, 3 H), 1.14 (d, J = 6.8 Hz, 6 H). m / z (ESI, + ve ion): 151.1 (M + H) ⁺ .

Step 2: 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide.
Oxalyl chloride (2M DCM solution, 7.4 mL, 14.7 mmol) in a slurry of THF solution (46 mL) of 2,5,6-trichloronicotinamide (intermediate P, 3.10 g, 13.8 mmol) at −78 ° C. Was slowly added with a syringe. The resulting slurry was heated at 60 ° C. for 3.5 hours, after which the heating was stopped and the reaction was cooled to −78 ° C. Triethylamine (6.0 mL, 42.6 mmol) was added, followed by a solution of 2-isopropyl-4-methylpyridine-3-amine (Intermediate R, 2.12 g, 14.1 mmol) added by cannula. The resulting slurry was warmed to room temperature, stirred for 1 hour and then partitioned between water (120 mL) and EtOAc (175 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in heptane / EtOAc (9: 1) and filtered. The solid matter after filtration was recovered to obtain 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.31 (s, 1 H), 9.54 (s, 1 H), 8.66 (s, 1 H), 8.34 (d, J = 4.8 Hz, 1 H), 7.16 (d, J = 5.0 Hz, 1 H), 3.24-3.33 (m, 1 H), 2.22 (s, 3 H) ), 1.17 (d, J = 6.6 Hz, 6 H). m / z (ESI, + ve ion): 400.9 (M + H) ⁺ .

Step 3: 6,7-Dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (55 mL) in ice-cold THF solution of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide (4.71 g, 11.7 mmol) 1M THF solution (23.5 mL, 23.5 mmol) was added slowly with a syringe. After 10 minutes, the ice bath was removed and the resulting solution was stirred for an additional 30 minutes at room temperature. The reaction was stopped with saturated aqueous ammonium chloride solution (125 mL) and extracted with EtOAc (250 mL). The organic layer was washed with brine (once), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-11% / DCM) and 6,7-dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d]. Pyrimidine-2,4 (1H, 3H) -dione was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.27 (br s, 1 H), 8.59 (s, 1 H), 8.52 (d, J = 5.0 Hz, 1 H) ), 7.28 (d, J = 5.0 Hz, 1H), 2.82-2.92 (m, 1H), 2.04 (s, 3H), 1.08 (d, J) = 6.6 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3 H). m / z (ESI, + ve ion): 365.0 (M + H) ⁺ .

Step 4: 4,6,7-Trichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
6,7-Dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (2.52 g, 6.9 mmol) ) DIPEA (1.80 mL, 10.3 mmol) followed by phosphorus oxychloride (1.58 mL, 10.3 mmol) was slowly added to the slurry of acetonitrile solution (45 mL) with a syringe. The resulting mixture was heated at 80 ° C. for 1.75 hours, then cooled to room temperature and concentrated to the 4,6,7-trichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyride. [2,3-d] Pyrimidine-2 (1H) -on was obtained. This material was used in subsequent steps without further purification.

Step 5: 4- (6,7-dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl ) -3-Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4,6,7-Trichloro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one (2.64 g, 6.9 mmol) DIPEA (3.61 mL, 20.7 mmol) was added to the THF solution (40 mL), then (S) -4-N-Boc-2-methylpiperazine (2.07 g, 10.3 mmol, Combi-Blocks, Inc., San Diego, CA, USA) was added. The resulting solution was stirred at room temperature for 1.5 hours, after which ice water (60 mL) was added. The mixture was stirred for an additional 5 minutes and then extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-11% / DCM) and 4- (6,7-dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo- 1,2-Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (dd, J = 11.6, 5.2 Hz, 2 H), 7.25 (d, J = 4.8 Hz, 1 H) ), 4.79-4.93 (m, 1H), 4.10-4.24 (m, 1H), 3.87-4.05 (m, 1H), 3.77-3. 87 (m, 1H), 3.62-3.76 (m, 1H), 2.99-3.25 (m, 2H), 2.55-2.69 (m, 1H), 1.94 (d, J = 2.5 Hz, 3H), 1.45 (s, 9H), 1.32 (br t, J = 5.7 Hz, 3H), 1.06 (d) , J = 6.8 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H). m / z (ESI, + ve ion): 547.2 (M + H) ⁺ .

Step 6: 4- (6-Chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyride [2,3- d] Pyrimidine-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl.
4- (6,7-dichloro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3 Potassium acetate (914 mg, 9.3 mmol) and (2-fluorophenyl) in a 1,4-dioxane solution (17 mL) of -methylpiperazin-1-carboxylic acid (S) -tert-butyl (1.02 g, 1.8 mmol). ) Boronic acid (313 mg, 2.2 mmol, Sigma-Aldrich, St. Louis, MO, USA) was added. Argon was blown into the mixture, after which [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (76 mg, 0.093 mmol) was added. Argon was blown into the mixture again and heated at 90 ° C. After 30 seconds, 3 drops of water were added to the reaction mixture. Heating was continued at 90 ° C. for 40 minutes, after which the reaction was cooled to room temperature. Water (50 mL) and brine (4 mL) were added and the resulting mixture was extracted with EtOAc (twice). The combined organic layers were washed with brine (once), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-9% / DCM) and 4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridine-3-3). Il) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.43 (d, J = 2.5 Hz, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 7. 47-7.55 (m, 1H), 7.16-7.33 (m, 4H), 4.86-4.97 (m, 1H), 4.21-4.30 (m, 1H), 3.90-4.06 (m, 2H), 3.80-3.89 (m, 1H), 3.67-3.78 (m, 1H), 3.04- 3.16 (m, 1H), 2.65-2.75 (m, 1H), 1.93 (s, 3H), 1.48 (s, 9H), 1.36 (br d) , J = 6.6 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.94 (dd, J = 6.6, 2.1 Hz, 3 H). m / z (ESI, + ve ion): 607.0 (M + H) ⁺ .

Step 7: 6-Chloro-7- (2-fluorophenyl) -1- (4-methyl-2- (2-propanil) -3-pyriminyl) -4-((2S) -2-methyl-4-( 2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
Trifluoroacetic acid (4.0 mL, 53.9 mmol), 4- (6-chloro-7- (2-fluorophenyl) -1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo -1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl (935 mg, 1.54 mmol) in a DCM solution (20 mL) added. The obtained solution was stirred at room temperature for 1.5 hours and then concentrated. The residue was dissolved in DCM (12 mL), cooled to 0 ° C. and treated with DIPEA (0.807 mL, 4.62 mmol) followed by acryloyl chloride (0.131 mL, 1.62 mmol; syringe dropwise). The resulting solution was stirred at 0 ° C. for 35 minutes, then the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (35 mL) and extracted with DCM (twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-11% / DCM) and 6-chloro-7- (2-fluorophenyl) -1- (4-methyl-2- (2-propanil) -3-. Pyrimidine) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (br d, J = 4.6 Hz, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 7 .47-7.55 (m, 1H), 7.16-7.34 (m, 4H), 6.78-6.94 (m, 1H), 6.15-6.26 (m) , 1H), 5.73-5.80 (m, 1H), 4.95 (br s, 1H), 4.36-4.45 (m, 0.5H), 4.24- 4.36 (m, 1.5 H), 4.11-4.21 (m, 0.5 H), 3.98-4.08 (m, 0.5 H), 3.71-3. 85 (m, 1H), 3.60-3.69 (m, 0.5H), 3.41-3.53 (m, 0.5H), 3.06-3.27 (m, 1 H), 2.65-2.75 (m, 1 H), 1.94 (d, J = 1.7 Hz, 3 H), 1.34 (d, J = 6.2 Hz, 3 H) ), 1.07 (d, J = 6.6 Hz, 3H), 0.94 (dd, J = 6.5, 0.9 Hz, 3H). m / z (ESI, + ve ion): 560.9 (M + H) ⁺ .

ステップ１：２，６−ジクロロ−５−フルオロニコチンアミド（中間体Ｓ）。
２，６−ジクロロ−５−フルオロ−ニコチン酸（４．０ｇ、１９．１ｍｍｏｌ、ＡｓｔａＴｅｃｈ Ｉｎｃ．、Ｂｒｉｓｔｏｌ、ＰＡ）の混合ジクロロメタン溶液（４８ｍＬ）に塩化オキサリル（２Ｍ ＤＣＭ溶液、１１．９ｍＬ、２３．８ｍｍｏｌ）に次いで、触媒量のＤＭＦ（０．０５ｍＬ）を加えた。反応物を室温で一晩撹拌し、その後、濃縮した。残渣を１，４−ジオキサン（４８ｍＬ）に溶解させ、０℃に冷却した。水酸化アンモニウム溶液（ＮＨ３ ２８．０〜３０％、３．６ｍＬ、２８．６ｍｍｏｌ）をシリンジでゆっくりと加えた。得られた混合物を０℃で３０分間撹拌し、その後、濃縮した。残渣をＥｔＯＡｃ／ヘプタンの１：１混合物で希釈して５分間撹拌し、その後、ろ過した。ろ過後の固形物を捨て、残った母液を体積が半分になるまで部分的に濃縮し、ろ過した。ろ過後の固形物をヘプタンで洗浄し、減圧オーブン（４５℃）で一晩乾燥させ、２，６−ジクロロ−５−フルオロニコチンアミドを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ ８．２３ （ｄ、Ｊ ＝ ７．９ Ｈｚ、１ Ｈ） ８．０９ （ｂｒ ｓ、１ Ｈ） ７．９３ （ｂｒ ｓ、１ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： ２１０．９ （Ｍ＋Ｈ）^＋。 Example 41
6-Fluoro-7- (2-Fluoro-6-Hydroxyphenyl) -1- (4-Methyl-2- (2-Propanil) -3-pyrimidine) -4-((2S) -2-Methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one

Step 1: 2,6-dichloro-5-fluoronicotinamide (Intermediate S).
Oxalyl chloride (2M DCM solution, 11.9 mL, 23.) in a mixed dichloromethane solution (48 mL) of 2,6-dichloro-5-fluoro-nicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc., Bristol, PA). 8 mmol) followed by a catalytic amount of DMF (0.05 mL). The reaction was stirred at room temperature overnight and then concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0 ° C. Ammonia hydroxide solution (NH3 28.0-30%, 3.6 mL, 28.6 mmol) was added slowly with a syringe. The resulting mixture was stirred at 0 ° C. for 30 minutes and then concentrated. The residue was diluted with a 1: 1 mixture of EtOAc / heptane, stirred for 5 minutes and then filtered. The solid matter after filtration was discarded, and the remaining mother liquor was partially concentrated until the volume was halved and filtered. The filtered solid was washed with heptane and dried in a vacuum oven (45 ° C.) overnight to give 2,6-dichloro-5-fluoronicotinamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.23 (d, J = 7.9 Hz, 1 H) 8.09 (br s, 1 H) 7.93 (br s, 1 H) .. m / z (ESI, + ve ion): 210.9 (M + H) ⁺ .

Step 2: 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide.
Oxalyl chloride (2M DCM solution, 14.4 mL, 28.8 mmol) in a slurry of ice-cooled THF solution (20 mL) of 2,6-dichloro-5-fluoronicotinamide (Intermediate S, 5.0 g, 23.9 mmol) ) Was added slowly with a syringe. The resulting mixture was heated at 75 ° C. for 1 hour, then the heating was stopped and the reaction was concentrated to half the volume. After cooling to 0 ° C., THF (20 mL) followed by a THF solution (10 mL) of 2-isopropyl-4-methylpyridine-3-amine (Intermediate R, 3.59 g, 23.92 mmol) was added dropwise by cannula. The resulting mixture was stirred at 0 ° C. for 1 hour, after which the reaction was stopped with a 1: 1 mixture of saline and saturated aqueous ammonium chloride solution. The mixture was extracted with EtOAc (3 times) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to concentrate 2,6-dichloro-5-fluoro-N- ((2-isopropyl-4-methylpyridine-3). -Il) Carbamoyl) Nicotinamide was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 385.1 (M + H) ⁺ .

Step 3: 7-Chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
In ice-cooled THF solution (40 mL) of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide (9.2 g, 24.0 mmol). KHMDS (1M THF solution, 50.2 mL, 50.2 mmol) was added slowly with a syringe. The ice bath was removed and the resulting mixture was stirred for 40 minutes at room temperature. The reaction was stopped with saturated aqueous ammonium chloride solution and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptane) and 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-3). Il) Pyrid [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.27 (br s, 1H), 8.48-8.55 (m, 2H), 7.29 (d, J = 4.8 Hz) , 1 H), 2.87 (quin, J = 6.6 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ: -126.90 (s, 1 F). m / z (ESI, + ve ion): 349.1 (M + H) ⁺ .

Step 4: 4,7-Dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
7-Chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (4.7 g, 13) Phosphoryl oxychloride (1.63 mL, 17.5 mmol) was added dropwise to an acetonitrile solution (20 mL) of .5 mmol) and DIPEA (3.5 mL, 20.2 mmol) with a syringe. The resulting mixture was heated at 80 ° C. for 1 hour, then cooled to room temperature and concentrated to the 4,7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) pyride. [2,3-d] Pyrimidine-2 (1H) -on was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 367.1 (M + H) ⁺ .

Step 5: 4- (7-Chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4 -Il) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
Ice-cooled 4,7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidin-2 (1H) -one (13.5 mmol) DIPEA (7.1 mL, 40.3 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (3.23 g, 16.1 mmol, Combi-Blocks, Inc.) in the acetonitrile solution (20 mL). San Diego, CA, USA) was added. The resulting mixture was warmed to room temperature, stirred for 1 hour and then diluted with saturated aqueous sodium hydrogen carbonate solution (200 mL) and EtOAc (300 mL). The mixture was stirred for an additional 5 minutes, separated into layers and the aqueous layer was extracted with additional EtOAc (once). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-50% / heptane) and 4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-. Oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. m / z (ESI, + ve ion): 531.2 (M + H) ⁺ .

Step 6: 4- (6-Fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [ 2,3-d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (7-Chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-Methylpiperazin-1-carboxylic acid (S) -tert-butyl (4.3 g, 8.1 mmol), potassium trifluoro (2-fluoro-6-hydroxyphenyl) borate (intermediate Q, 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (661 mg, 0.81 mmol) 1 , 4-Dichloromethane solution (80 mL) was degassed with nitrogen for 1 minute. Deoxidized water (14 mL) was added and the resulting mixture was heated at 90 ° C. for 1 hour. The reaction was cooled to room temperature, the reaction was stopped with semi-saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with EtOAc (2 times) and DCM (1 time). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-60% / heptane) and 4- (6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1-. (2-Isopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -Tert-Butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.19 (br s, 1 H), 8.38 (d, J = 5.0 Hz, 1 H), 8.26 (dd, J = 12.5, 9.2 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.18 (d, J = 5.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1H), 6.68 (t, J = 8.9 Hz, 1H), 4.77-4.98 (m, 1H), 4.24 (br t, J) = 14.2 Hz, 1 H), 3.93-4.08 (m, 1 H), 3.84 (br d, J = 12.9 Hz, 1 H), 3.52-3.75 ( m, 1H), 3.07-3.28 (m, 1H), 2.62-2.74 (m, 1H), 1.86-1.93 (m, 3H), 1. 43-1.48 (m, 9H), 1.35 (dd, J = 10.8, 6.8Hz, 3H), 1.26-1.32 (m, 1H), 1.07 (Dd, J = 6.6, 1.7 Hz, 3H), 0.93 (dd, J = 6.6, 2.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ: -115.65 (s, 1 F), -128.62 (s, 1 F). m / z (ESI, + ve ion): 607.3 (M + H) ⁺ .

Step 7: 6-Fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (4-methyl-2- (2-propanil) -3-pyridinyl) -4-((2S) -2-methyl -4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
Trifluoroacetic acid (25 mL, 324 mmol), 4- (6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridine-3-yl) -2-oxo -1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl (6.3 g, 10.4 mmol) in DCM solution (30 mL) ). The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCM (30 mL), cooled to 0 ° C., and a DCM solution of DIPEA (7.3 mL, 41.7 mmol) and acryloyl chloride (0.849 mL, 10.4 mmol) (3 mL; syringe dropwise). Processed sequentially with. The reaction was stirred at 0 ° C. for 10 minutes, then the reaction was stopped with semi-saturated aqueous sodium hydrogen carbonate solution and extracted with DCM (twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-100% / heptane) and 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (4-). Methyl-2- (2-propanyl) -3-pyridinyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 ( 1H) -On was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.20 (s, 1 H), 8.39 (d, J = 4.8 Hz, 1 H), 8.24-8.34 (m) , 1H), 7.23-7.32 (m, 1H), 7.19 (d, J = 5.0 Hz, 1H), 6.87 (td, J = 16.3, 11. 0 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 6.69 (t, J = 8.6 Hz, 1 H), 6.21 (br d, J = 16.2 Hz, 1H), 5.74-5.80 (m, 1H), 4.91 (br s, 1H), 4.23-4.45 (m, 2H), 3. 97-4.21 (m, 1H), 3.44-3.79 (m, 2H), 3.11-3-31 (m, 1H), 2.67-2.77 (m, 1 H), 1.91 (s, 3 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0. 94 (d, J = 6.8 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -115.64 (s, 1 F), -128.63 (s, 1 F). m / z (ESI, + ve ion): 561.2 (M + H) ⁺ .

ステップ１：２−シクロプロピル−４−メチルピリジン−３−アミン（中間体Ｔ）。
３−アミノ−２−ブロモ−４−ピコリン（４．０ｇ、２１．４ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）及びジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロリドパラジウム（ｉｉ）ジクロロメタン付加物（１．７８ｇ、２．１ｍｍｏｌ）のＴＨＦ溶液（１００ｍＬ）のスラリーにシクロプロピル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、６８．４ｍＬ、３４．２ｍｍｏｌ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ）を付加漏斗でゆっくりと加えた。得られた混合物を７０℃で６時間加熱し、その後、加熱を中止し、反応物を室温に冷却した。反応混合物の反応を５Ｎ ＮａＯＨ溶液で停止させ、ＥｔＯＡｃで抽出した（１回）。有機層を無水硫酸マグネシウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＥｔＯＡｃ−ＥｔＯＨ（３：１）０〜５０％／ヘプタン）で精製し、２−シクロプロピル−４−メチルピリジン−３−アミンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ｐｐｍ ７．８４ （ｄ、Ｊ ＝ ４．８ Ｈｚ、１ Ｈ）、６．８２ （ｄ、Ｊ ＝ ４．８ Ｈｚ、１ Ｈ）、３．８２ （ｂｒ ｓ、２ Ｈ）、２．１７ （ｓ、３ Ｈ）、１．８５ （ｑｕｉｎ、Ｊ ＝ ６．７ Ｈｚ、１ Ｈ）、０．９２−０．９９ （ｍ、４ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： １４９．１ （Ｍ＋Ｈ）^＋。 Example 42
1- (2-Cyclopropyl-4-methyl-3-pyrimidine) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-) Propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 2-Cyclopropyl-4-methylpyridine-3-amine (Intermediate T).
3-Amino-2-bromo-4-picoline (4.0 g, 21.4 mmol, Combi-Blocks, San Diego, CA, USA) and dichloro [1,1'-bis (diphenylphosphino) ferrocene] dichloromethane ( ii) Cyclopropyl zinc bromide (0.5 M THF solution, 68.4 mL, 34.2 mmol, Sigma-Aldrich, St. Louis, in a slurry of THF solution (100 mL) of dichloromethane adduct (1.78 g, 2.1 mmol). MO) was added slowly with an adduct. The resulting mixture was heated at 70 ° C. for 6 hours, then the heating was stopped and the reaction was cooled to room temperature. The reaction of the reaction mixture was stopped with 5N NaOH solution and extracted with EtOAc (1 time). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptan) to give 2-cyclopropyl-4-methylpyridine-3-amine. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 7.84 (d, J = 4.8 Hz, 1 H), 6.82 (d, J = 4.8 Hz, 1 H), 3.82 (Br s, 2H), 2.17 (s, 3H), 1.85 (quin, J = 6.7 Hz, 1H), 0.92-0.99 (m, 4H). m / z (ESI, + ve ion): 149.1 (M + H) ⁺ .

Step 2: 2,6-Dichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) -5-fluoronicotinamide.
Oxalyl chloride (2M DCM solution, 10.7 mL, 21.5 mmol) slowly in a THF solution (30 mL) of 2,6-dichloro-5-fluoronicotinamide (Intermediate S, 3.0 g, 14.4 mmol) with a syringe. Added. The resulting mixture was heated at 65 ° C. for 2 hours, then the heating was stopped and the reaction was concentrated. The residue was dissolved in THF (30 mL) and cannulated into a solution of 2-cyclopropyl-4-methylpyridine-3-amine (Intermediate T, 2.1 g, 14.4 mmol) in THF (105 mL). The resulting mixture was stirred at room temperature for 3 hours, then the reaction was stopped with water and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-50% / heptane) and 2,6-dichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) -5-fluoro. Obtained nicotinamide. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 9.85 (s, 1 H), 9.68 (s, 1 H), 8.29 (d, J = 4.8 Hz, 1 H), 7 .97 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 4.8 Hz, 1H), 2.29 (s, 3H), 2.08-2.16 (M, 1H), 1.08-1.13 (m, 2H), 0.95-1.02 (m, 2H). m / z (ESI, + ve ion): 383.0 (M + H) ⁺ .

Step 3: 7-Chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
Ice-cooled THF solution (30 mL) of 2,6-dichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) -5-fluoronicotinamide (3.35 g, 8.7 mmol) KHMDS (1M THF solution, 17.5 mL, 17.5 mmol) was slowly added to the mixture with a syringe. The ice bath was removed and the resulting mixture was stirred for 14 hours at room temperature. The reaction was stopped with saturated aqueous ammonium chloride solution and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and 7-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido [2,3-d] pyrimidine-2. , 4 (1H, 3H) -dione was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 347.0 (M + H) ⁺ .

Step 4: 4,7-Dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido [2,3-d] pyrimidin-2 (1H) -one.
7-Chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (8.7 mmol) and Phosphoryl oxychloride (1.22 mL, 13.1 mmol) was added dropwise to an acetonitrile solution (25 mL) of DIPEA (2.32 mL, 13.1 mmol) with a syringe. The resulting mixture was heated at 80 ° C. for 3 hours, then cooled to room temperature and concentrated to concentrate 4,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido. [2,3-d] Pyrimidine-2 (1H) -on was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 365.0 (M + H) ⁺ .

Step 5: 4- (7-Chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin- 4-Il) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4,7-Dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoropyrido [2,3-d] pyrimidine-2 (1H) -one (8.7 mmol) ice-cooled DIPEA (7.74 mL, 43.7 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (1.75 g, 8.7 mmol, Combi-Blocks, Inc.) in the DCM solution (25 mL). San Diego, CA, USA) was added. The resulting mixture was stirred at 0 ° C. for 2 hours, then the reaction was stopped with water and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-60% / heptane) and 4- (7-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-2. -Oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.31-8.39 (m, 2 H), 7.18 (d, J = 4.8 Hz, 1 H), 4.82 (br) s, 1H), 4.10-4.21 (m, 1H), 3.96 (br s, 1H), 3.82 (br d, J = 13.3 Hz, 1H), 3 .62-3.72 (m, 1H), 3.19-3.52 (m, 2H), 1.94 (s, 3H), 1.62 (dq, J = 8.2, 4) .0 Hz, 1 H), 1.45 (s, 9 H), 1.32 (dd, J = 6.5, 3.6 Hz, 3 H), 0.87-0.98 (m, 1) H), 0.69-0.84 (m, 2H), 0.57-0.68 (m, 1H). m / z (ESI, + ve ion): 529.0 (M + H) ⁺ .

Step 6: 4- (1- (2-Cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -2-oxo-1,2-dihydropyrimide [2,3-d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (7-Chloro-1- (2-Cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl ) -3-Methylpiperazin-1-carboxylic acid (S) -tert-butyl (987 mg, 1.87 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (524 mg, 3.36 mmol, Combi-Blocks, San 1 of a mixture of Diego, CA, USA), potassium acetate (916 mg, 9.33 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (152 mg, 0.19 mmol). , 4-Dichloromethane solution (10 mL) was blown with argon and heated at 80 ° C. After 2 minutes, 3 drops of water were added to the reaction mixture to raise the temperature to 90 ° C. Heating was continued at 90 ° C. for 1 hour, after which the reaction was cooled to room temperature. Water was added and the resulting mixture was extracted with EtOAc (3 times). The combined organic layers were washed with brine (once), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-65% / heptan) and 4- (1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-7- (2-). Fluoro-6-hydroxyphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl was obtained. .. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.22 (s, 1 H), 8.19-8.31 (m, 2 H), 7.23-7.32 (m, 1 H) ), 7.10 (d, J = 5.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (t, J = 8.8 Hz, 1) H) 4.76-4.98 (m, 1H) 4.15-4.31 (m, 1H) 3.99 (br s, 1H) 3.78-3.89 ( m, 1H), 3.55-3.77 (m, 1H), 2.99-3.29 (m, 2H), 1.91 (d, J = 2.7 Hz, 3H) , 1.68 (td, J = 8.0, 4.5 Hz, 1 H), 1.45 (s, 9 H), 1.35 (dd, J = 18.7, 6.6 Hz, 3 H), 0.82-0.89 (m, 1H), 0.71-0.82 (m, 2H), 0.57-0.66 (m, 1H). m / z (ESI, + ve ion): 605.0 (M + H) ⁺ .

Step 7: 1- (2-Cyclopropyl-4-methyl-3-pyridinyl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-Propenoyl) -1-piperazinyl) Pyrid [2,3-d] Pyrimidine-2 (1H) -on.
Trifluoroacetic acid (2.17 mL, 28.1 mmol), 4- (1- (2-cyclopropyl-4-methylpyridine-3-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) ) -2-Oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl (850 mg, 1.41 mmol) DCM It was added to the solution (10 mL). The resulting mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in DCM (10 mL) and cooled to 0 ° C., and Acryloyl chloride (0.103 mL, 1.27 mmol) was added dropwise with a syringe after DIPEA (1.23 mL, 7.03 mmol) for treatment. The reaction was stirred at 0 ° C. for 2 hours, then the reaction was stopped with water and extracted with DCM (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-80% / heptan) and 1- (2-cyclopropyl-4-methyl-3-pyridinyl) -6-fluoro-7. -(2-Fluoro-6-Hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H)- Got on. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.32 (br t, J = 10.1 Hz, 1 H), 8.28 (d, J = 5.0 Hz, 1 H), 7 .51-7.60 (m, 1H), 7.27-7.38 (m, 3H), 7.14 (d, J = 4.8Hz, 1H), 6.80-6. 92 (m, 1H), 6.20 (br d, J = 16.6 Hz, 1 H) 5.69-5.80 (m, 1 H), 4.92 (br d, J = 1) .5 Hz, 1H), 4.24-4.46 (m, 2H), 3.97-4.19 (m, 1H), 3.71 (br s, 1H), 3.42 -3.66 (m, 1H), 3.05-3.30 (m, 1H), 1.97 (s, 3H), 1.65 (br s, 1H), 1.33 ( d, J = 6.6 Hz, 3H), 0.90 (td, J = 5.4, 2.6 Hz, 1H), 0.80-0.87 (m, 1H), 0. 70-0.79 (m, 1H), 0.60-0.70 (m, 1H). m / z (ESI, + ve ion): 559.0 (M + H) ⁺ .

ステップ１：４，６−ジイソプロピルピリミジン−５−アミン（中間体Ｕ）。
４，６−ジクロロ−５−アミノピリミジン（３．００ｇ、１８．２９ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ Ｉｎｃ．、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）のＴＨＦ溶液（１８ｍＬ）の混合物中にアルゴン気泡を５分間吹き込み脱酸素処理をした。２−プロピル亜鉛ブロミド（０．５Ｍ ＴＨＦ溶液、９１．０ｍＬ、４５．５ｍｍｏｌ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ）、次いでＸａｎｔＰｈｏｓ Ｐｄ Ｇ３（４３４ｍｇ、０．４６ｍｍｏｌ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ、ＵＳＡ）をシリンジで加えた。得られた混合物を室温で１６時間撹拌し、その後、セライトパッドに通してろ過した。ろ滓をＥｔＯＡｃですすぎ、ろ液を回収して濃縮し、４，６−ジイソプロピルピリミジン−５−アミン（３．４５ｇ）が得られた。この物質を、さらに精製することなく以降のステップで使用した。ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： １８０．２ （Ｍ＋Ｈ）^＋。 Example 43
6-Chloro-1- (4,6-di (2-propanil) -5-pyrimidineyl) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl)) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 4,6-diisopropylpyrimidine-5-amine (intermediate U).
Deoxygen scavenger by blowing argon bubbles into a mixture of 4,6-dichloro-5-aminopyrimidine (3.00 g, 18.29 mmol, Combi-Blocks Inc., San Diego, CA, USA) in THF solution (18 mL) for 5 minutes. Processed. 2-propyl zinc bromide (0.5 M THF solution, 91.0 mL, 45.5 mmol, Sigma-Aldrich, St. Louis, MO), followed by Xantphos Pd G3 (434 mg, 0.46 mmol, Sigma-Aldrich, St. Louis, MO, USA) was added with a syringe. The resulting mixture was stirred at room temperature for 16 hours and then filtered through a Celite pad. The slag was rinsed with EtOAc and the filtrate was collected and concentrated to give 4,6-diisopropylpyrimidine-5-amine (3.45 g). This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 180.2 (M + H) ⁺ .

Step 2: 2,5,6-trichloro-N-((4,6-diisopropylpyrimidine-5-yl) carbamoyl) nicotinamide.
Treatment of 1,2-dichloroethane solution (49 mL) of 2,5,6-trichloronicotinamide (intermediate P, 3.30 g, 14.6 mmol) with oxalyl chloride (2M DCM solution, 11.0 mL, 22.0 mmol) did. The mixture was heated at 80 ° C. for 45 minutes, then the heating was stopped and the reaction was concentrated. The residue is dissolved in acetonitrile (49 mL), cooled to -10 ° C., and an acetonitrile solution (5 mL) of 4,6-diisopropylpyrimidine-5-amine (intermediate U, 3.15 g, 17.6 mmol) is added by cannula. It was. The resulting mixture was stirred at room temperature overnight and then concentrated. The residue was suspended in warm heptane / EtOAc (10: 1) (110 mL) and filtered. The filtrate is concentrated and the residue is purified by silica gel chromatography (eluent: EtOAc 0-40% / heptane) with 2,5,6-trichloro-N-((4,6-diisopropylpyrimidine-5-yl) carbamoyl). ) Nicotinamide was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.30-11.46 (m, 1 H), 9.66 (br s, 1 H), 8.95-9.01 (m, 1) H), 8.65-8.72 (m, 1 H), 3.26 (s, 2 H), 1.17 (d, J = 6.6 Hz, 12 H). m / z (ESI, + ve ion): 432.0 (M + H) ⁺ .

Step 3: 6,7-Dichloro-1- (4,6-diisopropylpyrimidine-5-yl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -dione.
KHMDS (1M) in a THF solution (49 mL) of 2,5,6-trichloro-N-((4,6-diisopropylpyrimidine-5-yl) carbamoyl) nicotinamide (2.10 g, 4.9 mmol) at -20 ° C. THF solution, 12.2 mL, 12.2 mmol) was added. The cooling bath was removed and the resulting mixture was stirred for 2 hours at room temperature. The reaction of the reaction mixture was stopped with saturated aqueous ammonium chloride solution (50 mL), diluted with brine and extracted with EtOAc / MeOH (3: 1) (once). It was separated into layers and the aqueous layer was extracted with additional EtOAc (once). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in heptane / EtOAc and filtered. The filtrate was concentrated to give 6,7-dichloro-1- (4,6-diisopropylpyrimidine-5-yl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -dione. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.33 (s, 1 H), 9.18 (s, 1 H), 8.61 (s, 1 H), 2.90-3. 02 (m, 2 H), 1.10 (d, J = 6.6 Hz, 6 H), 0.99 (d, J = 6.6 Hz, 6 H). m / z (ESI, + ve ion): 394.0 (M + H) ⁺ .

Step 4: 4- (6,7-dichloro-1- (4,6-diisopropylpyrimidine-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl)- 3-Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
6,7-Dichloro-1- (4,6-diisopropylpyrimidine-5-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (900 mg, 2.28 mmol) and DIPEA ( Phosphorus oxychloride (0.255 mL, 2.74 mmol) was slowly added to an acetonitrile solution (15 mL) of 0.518 mL, 2.97 mmol) with a syringe. The resulting mixture was heated at 80 ° C. for 45 minutes and then cooled to −10 ° C. DIPEA (1.2 mL, 6.88 mmol), followed by (S) -4-N-Boc-2-methylpiperazine (1.37 g, 6.85 mmol, Combi-Blocks, Inc., San Diego, CA, USA). Acetonitrile solution (5 mL) was added by cannula. The resulting mixture was warmed to room temperature and stirred for 10 minutes, after which additional DIPEA (1.2 mL, 6.88 mmol) was added. The reaction mixture was poured into ice water and extracted with EtOAc (twice). The combined organic layers were washed with brine (once), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-80% / heptane) and 4- (6,7-dichloro-1- (4,6-diisopropylpyrimidine-5-yl) -2-oxo-1, 2-Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.15 (s, 1 H), 8.48 (s, 1 H), 5.75 (s, 1 H), 4.90 (br s) , 1 H), 4.21 (br d, J = 14.1 Hz, 1 H), 3.91-4.06 (m, 1 H), 3.83 (br d, J = 13.3 Hz) , 1H), 3.73 (br t, J = 10.6 Hz, 1H), 3.03-3.19 (m, 1H), 2.69 (dq, J = 13.4, 6) .7 Hz, 2 H), 1.45 (s, 9 H), 1.31-1.36 (m, 3 H), 1.09 (d, J = 6.6 Hz, 6 H), 1 .00 (d, J = 6.6 Hz, 6 H). m / z (ESI, + ve ion): 576.2 (M + H) ⁺ .

Step 5: 4- (6-chloro-1- (4,6-diisopropylpyrimidine-5-yl) -7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4- (6,7-dichloro-1- (4,6-diisopropylpyrimidine-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methyl Mixture of piperazine-1-carboxylic acid (S) -tert-butyl (500 mg, 0.87 mmol) and potassium acetate (426 mg, 4.34 mmol) Argon bubbles in a mixture of 1,4-dioxane solution (4.3 mL) Was blown in for 5 minutes to deoxidize. [1,1'-Bis (diphenylphosphino) ferrocene] Dichloropalladium (II) dichloromethane complex (63 mg, 0.087 mmol) was added, and the mixture was heated at 90 ° C. for 10 minutes. A solution of 1,4-dioxane (2 mL) of 2-fluorophenylboronic acid (243 mg, 1.735 mmol, Combi-Blocks, Inc., San Diego, CA, USA) was slowly added, followed by 6 drops of water. The resulting mixture was heated at 90 ° C. for 1 hour. The reaction mixture was adsorbed on a silica gel plug, purified by silica gel chromatography (eluent: MeOH 0-8% / DCM), and 4- (6-chloro-1- (4,6-diisopropylpyrimidine-5-yl)-. Obtained 7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl. It was. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.05 (s, 1 H), 8.46 (s, 1 H), 8.15 (s, 1 H), 7.49-7. 54 (m, 1H), 7.27-7.32 (m, 1H), 7.12-7.16 (m, 1H), 4.93 (br s, 1H), 4.29 (Br d, J = 13.9 Hz, 1 H) 4.07 (br d, J = 4.6 Hz, 1 H) 3.85 (br d, J = 13.7 Hz, 1 H) 3.75 (br t, J = 11.0 Hz, 1 H), 3.56 (s, 2 H), 3.08-3.22 (m, 3 H), 2.67-2.78 (M, 2 H), 1.45 (s, 9 H), 1.08 (d, J = 6.6 Hz, 6 H), 0.92 (d, J = 6.6 Hz, 6 H) .. m / z (ESI, + ve ion): 636.2 (M + H) ⁺ .

Step 6.6-Chloro-1- (4,6-di (2-propanil) -5-pyrimidineyl) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2) -Propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on.
Trifluoroacetic acid (0.176 mL, 2.36 mmol), 4- (6-chloro-1- (4,6-diisopropylpyrimidine-5-yl) -7- (2-fluorophenyl) -2-oxo-1 , 2-Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl (150 mg, 0.24 mmol) in DCM solution (2.4 mL) added. The resulting mixture was heated at 38 ° C. for 2 hours and then concentrated. The residue was dissolved in DCM (2.4 mL), cooled to 0 ° C. and treated with DIPEA (0.494 mL, 2.83 mmol). After 2 minutes, acryloyl chloride (0.019 mL, 0.24 mmol) was added dropwise with a syringe and the reaction was stirred at 0 ° C. for an additional 10 minutes. The reaction mixture was concentrated and the residue was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc (twice). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-100% / heptane followed by MeOH 0-8% / DCM) and 6-chloro-1- (4,6-di (2-propanil) -5-pyrimidineyl). ) -7- (2-Fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one Got ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.06 (s, 1 H), 8.46-8.52 (m, 1 H), 7.48-7.55 (m, 1 H) ), 7.26-7.34 (m, 2H), 7.17 (td, J = 7.4, 1.6 Hz, 1H), 6.82-6.93 (m, 1H) , 6.22 (br d, J = 16.6 Hz, 1 H), 5.75-5.80 (m, 1 H), 5.00 (br s, 1 H), 4.31-4. 43 (m, 2H), 4.02-4.21 (m, 1H), 3.81 (br d, J = 8.9 Hz, 1H), 3.45-3.70 (m, 1 H), 3.10-3.30 (m, 1 H), 2.73 (br d, J = 6.4 Hz, 2 H), 1.36 (d, J = 6.6 Hz, 3 H), 1.09 (d, J = 6.6 Hz, 6 H), 0.93 (d, J = 6.4 Hz, 6 H). m / z (ESI, + ve ion): 590.2 (M + H) ⁺ .

ステップ１：２，５，６−トリクロロ−Ｎ−（（２−シクロプロピル−４−メチルピリジン−３−イル）カルバモイル）ニコチンアミド。
２，５，６−トリクロロニコチンアミド（中間体Ｐ、３．５ｇ、１５．５ｍｍｏｌ）のＴＨＦ溶液（３０ｍＬ）に塩化オキサリル（２Ｍ ＤＣＭ溶液、１１．６ｍＬ、２３．３ｍｍｏｌ）をシリンジでゆっくりと加えた。得られた混合物を６５℃で２時間加熱し、その後、加熱を中止し、反応物を濃縮した。残渣をＴＨＦ（３０ｍＬ）に溶解させ、カニューレで２−シクロプロピル−４−メチルピリジン−３−アミン（中間体Ｔ、２．５ｇ、１７．１ｍｍｏｌ）のＴＨＦ溶液（１５ｍＬ）で処理した。得られた混合物を室温で２時間撹拌し、その後、水で反応を停止させ、ＥｔＯＡｃで抽出した（３回）。合わせた有機層を無水硫酸ナトリウムで乾燥させて濃縮し、２，５，６−トリクロロ−Ｎ−（（２−シクロプロピル−４−メチルピリジン−３−イル）カルバモイル）ニコチンアミドを得た。この物質を、さらに精製することなく以降のステップで使用した。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ １１．３０ （ｂｒ ｓ、１ Ｈ）、９．４４−９．７３ （ｍ、１ Ｈ）、８．６４ （ｓ、１ Ｈ）、８．２１ （ｄ、Ｊ ＝ ５．０ Ｈｚ、１ Ｈ）、７．０７ （ｄ、Ｊ ＝ ５．０ Ｈｚ、１ Ｈ）、２．２２ （ｓ、３ Ｈ）、０．９２ （ｓ、２ Ｈ）、０．９１ （ｄ、Ｊ ＝ ３．５ Ｈｚ、２ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： ４００．９ （Ｍ＋Ｈ）^＋。 Example 44
6-Chloro-1- (2-Cyclopropyl-4-methyl-3-pyrimidine) -7- (2-Fluoro-6-Hydroxyphenyl) -4-((2S) -2-Methyl-4- (2-) Propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 2,5,6-trichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide.
Slowly add oxalyl chloride (2M DCM solution, 11.6 mL, 23.3 mmol) to a THF solution (30 mL) of 2,5,6-trichloronicotinamide (intermediate P, 3.5 g, 15.5 mmol) with a syringe. It was. The resulting mixture was heated at 65 ° C. for 2 hours, then the heating was stopped and the reaction was concentrated. The residue was dissolved in THF (30 mL) and treated with a cannula in THF (15 mL) of 2-cyclopropyl-4-methylpyridine-3-amine (Intermediate T, 2.5 g, 17.1 mmol). The resulting mixture was stirred at room temperature for 2 hours, then the reaction was stopped with water and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2,5,6-trichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide. This material was used in subsequent steps without further purification. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.30 (br s, 1 H), 9.44-9.73 (m, 1 H), 8.64 (s, 1 H), 8 .21 (d, J = 5.0 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 2.22 (s, 3H), 0.92 (s, 2) H), 0.91 (d, J = 3.5 Hz, 2 H). m / z (ESI, + ve ion): 400.9 (M + H) ⁺ .

Step 2: 6,7-Dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M) in ice-cold THF solution (5 mL) of 2,5,6-trichloro-N-((2-cyclopropyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide (460 mg, 1.15 mmol) THF solution (2.30 mL, 2.30 mmol) was added slowly with a syringe. The resulting mixture was stirred at 0 ° C. for 2 hours, then the reaction was stopped with saturated aqueous ammonium chloride solution and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-40% / heptane) and 6,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl). ) Pyrid [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.26 (br s, 1 H), 8.59 (s, 1 H), 8.36 (d, J = 5.0 Hz, 1 H) ), 7.19 (d, J = 5.0 Hz, 1H), 2.05 (s, 3H), 1.86-1.96 (m, 1H), 0.88-0.95 (M, 1H), 0.79-0.87 (m, 1H), 0.73-0.79 (m, 1H), 0.62-0.70 (m, 1H). m / z (ESI, + ve ion): 362.9 (M + H) ⁺ .

Step 3: 4,6,7-Trichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
6,7-Dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (4.60 g, 12. Phosphoryl oxychloride (1.77 mL, 19.0 mmol) was added to an acetonitrile solution (25 mL) of 7 mmol) and DIPEA (3.32 mL, 19.0 mmol). The resulting mixture was heated at 80 ° C. for 3 hours, then cooled to room temperature and concentrated to the 4,6,7-trichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) pyride [ 2,3-d] Pyrimidine-2 (1H) -on was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 380.9 (M + H) ⁺ .

Step 4: 4- (6,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4- Il) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl (intermediate V).
4,6,7-Trichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidin-2 (1H) -one (12.7 mmol) ice-cooled In DCM solution (40 mL), DIPEA (11.1 mL, 63.3 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (2.54 g, 12.7 mmol, Combi-Blocks, Inc., San. Diego, CA, USA) was added. The resulting mixture was stirred at 0 ° C. for 1 hour, then the reaction was stopped with water and extracted with DCM (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptan) and 4- (6,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-). 3-Il) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.44 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7. 17 (d, J = 5.2 Hz, 1 H), 4.85 (br s, 1 H), 4.16 (br d, J = 11.0 Hz, 1 H), 3.96 (br dd) , J = 3.4, 2.2 Hz, 1 H), 3.82 (br d, J = 13.3 Hz, 1 H), 3.69 (q, J = 12.0 Hz, 1 H) 3.19-3.29 (m, 1H), 3.03-3.19 (m, 1H), 1.95 (d, J = 3.9 Hz, 3H), 1.58- 1.68 (m, 1H), 1.45 (s, 9H), 1.32 (dd, J = 6.6, 2.5Hz, 3H), 0.88-0.97 (m) , 1H), 0.77-0.86 (m, 1H), 0.70-0.77 (m, 1H), 0.59-0.69 (m, 1H). m / z (ESI, + ve ion): 544.9 (M + H) ⁺ .

Step 5: 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -7- (2-fluoro-6-hydroxyphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (6,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl)- 3-Methylpiperazin-1-carboxylic acid (S) -tert-butyl (intermediate V, 992 mg, 1.82 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (510 mg, 3.27 mmol, Combi-Blocks) , San Diego, CA, USA), potassium acetate (892 mg, 9.09 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (119 mg, 0.15 mmol). The 1,4-dioxane solution (16 mL) of the above was degassed with argon and heated at 80 ° C. After 2 minutes, 2 drops of water were added to the reaction mixture to raise the temperature to 90 ° C. Heating was continued at 90 ° C. for 1 hour, after which the reaction was cooled to room temperature. Water was added and the resulting mixture was extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptan) and 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-3). Il) -7- (2-fluoro-6-hydroxyphenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) ) -Tert-Butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.04-10.22 (m, 1 H), 8.31-8.45 (m, 1 H), 8.23 (d, J = 5.0 Hz, 1 H), 7.19-7.31 (m, 1 H), 7.09 (br s, 1 H), 6.60-6.76 (m, 2 H), 4. 75-5.02 (m, 1H), 4.10-4.36 (m, 1H), 3.92-4.06 (m, 1H), 3.56-3.89 (m, 2H), 2.91-3.30 (m, 2H), 1.90 (br d, J = 19.3 Hz, 3H), 1.61-1.77 (m, 1H), 1.45 (s, 9H), 1.30-1.40 (m, 3H), 0.59-0.90 (m, 4H). m / z (ESI, + ve ion): 620.9 (M + H) ⁺ .

Step 6: 1- (2-Cyclopropyl-4-methyl-3-pyridinyl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-Propenoyl) -1-piperazinyl) Pyrid [2,3-d] Pyrimidine-2 (1H) -on.
Trifluoroacetic acid (2.47 mL, 33.2 mmol), 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -7- (2-fluoro-6-hydroxyphenyl) ) -2-Oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl (1.03 g, 1.66 mmol) Was added to the DCM solution (10 mL). The resulting mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in DCM (10 mL), cooled to 0 ° C., and treated with DIPEA (1.45 mL, 8.29 mmol) followed by acryloyl chloride (0.120 mL, 1.49 mmol) by syringe. The reaction was stirred at 0 ° C. for 2 hours, then the reaction was stopped with water and extracted with DCM (3 times). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptane) and 6-chloro-1- (2-cyclopropyl-4-methyl-3-pyridinyl) -7. -(2-Fluoro-6-Hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H)- Got on. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.06-10.26 (m, 1 H), 8.33-8.49 (m, 1 H), 8.23 (d, J = 4.8 Hz, 1 H), 7.20-7.34 (m, 1 H), 7.09 (br d, J = 2.1 Hz, 1 H), 6.79-6.92 (m) , 1H), 6.63-6.78 (m, 2H), 6.16-6.29 (m, 1H), 5.76 (dd, J = 10.4, 2.3 Hz, 1H), 4.77-5.08 (m, 1H), 4.21-4.47 (m, 2H), 3.98-4.20 (m, 1H), 3.39- 3.92 (m, 2H), 2.92-3.28 (m, 1H), 1.85-1.99 (m, 3H), 1.62-1.79 (m, 1H) ), 1.34 (br d, J = 19.5 Hz, 3H), 0.74-0.88 (m, 3H), 0.56-0.68 (m, 1H). m / z (ESI, + ve ion): 574.9 (M + H) ⁺ .

ステップ１：４−（６−クロロ−１−（２−シクロプロピル−４−メチルピリジン−３−イル）−７−（２−フルオロフェニル）−２−オキソ−１，２−ジヒドロピリド［２，３−ｄ］ピリミジン−４−イル）−３−メチルピペラジン−１−カルボン酸（Ｓ）−ｔｅｒｔ−ブチル。
４−（６，７−ジクロロ−１−（２−シクロプロピル−４−メチルピリジン−３−イル）−２−オキソ−１，２−ジヒドロピリド［２，３−ｄ］ピリミジン−４−イル）−３−メチルピペラジン−１−カルボン酸（Ｓ）−ｔｅｒｔ−ブチル（中間体Ｖ、５００ｍｇ、０．９２ｍｍｏｌ）、（２−フルオロフェニル）ボロン酸（２６９ｍｇ、１．９２ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）、酢酸カリウム（４５０ｍｇ、４．５８ｍｍｏｌ）、及び［１，１′−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（７５ｍｇ、０．０９ｍｍｏｌ）の混合物の１，４−ジオキサン溶液（７ｍＬ）をアルゴンで脱気し、８０℃で加熱した。２分後、水３滴を反応混合物に加え、温度を９０℃に昇温させた。加熱を９０℃で１時間継続し、その後、反応物を室温に冷却した。水を加え、得られた混合物をＥｔＯＡｃで抽出した（３回）。合わせた有機層を無水硫酸マグネシウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＥｔＯＡｃ−ＥｔＯＨ（３：１）０〜４０％／ヘプタン）で精製し、４−（６−クロロ−１−（２−シクロプロピル−４−メチルピリジン−３−イル）−７−（２−フルオロフェニル）−２−オキソ−１，２−ジヒドロピリド［２，３−ｄ］ピリミジン−４−イル）−３−メチルピペラジン−１−カルボン酸（Ｓ）−ｔｅｒｔ−ブチルを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ ８．４１ （ｄ、Ｊ ＝ ２．５ Ｈｚ、１ Ｈ）、８．２５ （ｄ、Ｊ ＝ ５．０ Ｈｚ、１ Ｈ）、７．４９−７．５６ （ｍ、１ Ｈ）、７．２５−７．３５ （ｍ、３ Ｈ）、７．１１ （ｄ、Ｊ ＝ ４．８ Ｈｚ、１ Ｈ）、４．９０ （ｂｒ ｄ、Ｊ ＝ １．５ Ｈｚ、１ Ｈ）、４．２４ （ｂｒ ｄ、Ｊ ＝ １３．７ Ｈｚ、１ Ｈ）、３．９３−４．０７ （ｍ、１ Ｈ）、３．８５ （ｂｒ ｄ、Ｊ ＝ １３．９ Ｈｚ、１ Ｈ）、３．６５−３．７９ （ｍ、１ Ｈ）、３．２１−３．３０ （ｍ、１ Ｈ）、３．０９−３．２０ （ｍ、１ Ｈ）、１．９６ （ｓ、３ Ｈ）、１．６０−１．７０ （ｍ、１ Ｈ）、１．４５ （ｓ、９ Ｈ）、１．３６ （ｄ、Ｊ ＝ ６．６ Ｈｚ、３ Ｈ）、０．８６−０．９３ （ｍ、１ Ｈ）、０．７２−０．８３ （ｍ、２ Ｈ）、０．６１−０．７１ （ｍ、１ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： ６０５．０ （Ｍ＋Ｈ）^＋。 Example 45
6-Chloro-1- (2-Cyclopropyl-4-methyl-3-pyrimidine) -7- (2-Fluorophenyl) -4-((2S) -2-Methyl-4- (2-propenoyl) -1 -Piperadinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -7- (2-fluorophenyl) -2-oxo-1,2-dihydropyride [2,3] -D] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4- (6,7-dichloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl)- 3-Methylpiperazin-1-carboxylic acid (S) -tert-butyl (intermediate V, 500 mg, 0.92 mmol), (2-fluorophenyl) boronic acid (269 mg, 1.92 mmol, Combi-Blocks, San Diego, CA, USA), potassium acetate (450 mg, 4.58 mmol), and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (75 mg, 0.09 mmol) 1,4 -Dichloromethane solution (7 mL) was degassed with argon and heated at 80 ° C. After 2 minutes, 3 drops of water were added to the reaction mixture to raise the temperature to 90 ° C. Heating was continued at 90 ° C. for 1 hour, after which the reaction was cooled to room temperature. Water was added and the resulting mixture was extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-40% / heptane) and 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-3). Il) -7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert- Obtained butyl. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.41 (d, J = 2.5 Hz, 1 H), 8.25 (d, J = 5.0 Hz, 1 H), 7. 49-7.56 (m, 1H), 7.25-7.35 (m, 3H), 7.11 (d, J = 4.8 Hz, 1H), 4.90 (br d, J = 1.5 Hz, 1 H), 4.24 (br d, J = 13.7 Hz, 1 H), 3.93-4.07 (m, 1 H), 3.85 (br d, J = 13.9 Hz, 1H) 3.65-3.79 (m, 1H), 3.21-3.30 (m, 1H), 3.09-3.20 (m, 1) H) 1.96 (s, 3H), 1.60-1.70 (m, 1H), 1.45 (s, 9H), 1.36 (d, J = 6.6 Hz, 3 H), 0.86-0.93 (m, 1 H), 0.72-0.83 (m, 2 H), 0.61-0.71 (m, 1 H). m / z (ESI, + ve ion): 605.0 (M + H) ⁺ .

Step 2: 6-Chloro-1- (2-cyclopropyl-4-methyl-3-pyrimidine) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) ) -1-Piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on.
Trifluoroacetic acid (1.28 mL, 17.2 mmol), 4- (6-chloro-1- (2-cyclopropyl-4-methylpyridine-3-yl) -7- (2-fluorophenyl) -2- DCM solution (10 mL) of oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl (521 mg, 0.86 mmol) In addition to. The resulting mixture was stirred at room temperature for 3 hours and then concentrated. The residue was dissolved in DCM (10 mL) and cooled to 0 ° C., and DIPEA (0.762 mL, 4.31 mmol) followed by acryloyl chloride (0.440 mL, 0.86 mmol) was added dropwise with a syringe for treatment. The reaction was stirred at 0 ° C. for 2 hours, then the reaction was stopped with water and extracted with DCM (1 time). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptane) and 6-chloro-1- (2-cyclopropyl-4-methyl-3-pyridinyl) -7. -(2-Fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained. .. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.44 (br s, 1 H), 8.25 (d, J = 5.0 Hz, 1 H), 7.48-7.56 ( m, 1H), 7.24-7.35 (m, 3H), 7.11 (d, J = 5.0 Hz, 1H), 6.78-6.92 (m, 1H) , 6.20 (br d, J = 16.2 Hz, 1 H), 5.72-5.79 (m, 1 H), 4.94 (br s, 1 H), 4.25-4. 44 (m, 2H), 3.99-4.20 (m, 1H), 3.43-3.69 (m, 2H), 3.02-3.15 (m, 1H), 1.96 (d, J = 3.3 Hz, 3H), 1.60-1.71 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 0. 89 (br dd, J = 8.3, 4.6 Hz, 1 H), 0.72-0.84 (m, 2 H), 0.61-0.71 (m, 1 H). m / z (ESI, + ve ion): 559.0 (M + H) ⁺ .

ステップ１：２−エチル−４−メチルピリジン−３−アミン（中間体Ｗ）。
臭化エチルマグネシウム（３Ｍジエチルエーテル溶液、３．５ｍＬ、１０．５ｍｍｏｌ）を、塩化亜鉛溶液（０．５Ｍ ＴＨＦ溶液、１８ｍＬ、９．０ｍｍｏｌ）にシリンジでゆっくりと加えた。添加は発熱的であった。溶液を室温で１０分間撹拌し、その後、３−アミノ−２−ブロモ−４−ピコリン（１．５ｇ、８．０ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）及びジクロロ［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロリドパラジウム（ｉｉ）ジクロロメタン付加物（１２０ｍｇ、０．１６ｍｍｏｌ）を加えた。得られた混合物を５０℃で２０分間加熱し、その後、加熱を中止し、反応物を室温に冷却した。反応混合物の反応を１０％水酸化アンモニウム溶液（３０ｍＬ）で停止させ、ＥｔＯＡｃで抽出した（８０ｍＬ、次いで４０ｍＬで２回）。合わせた有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＭｅＯＨ１〜５％／ＤＣＭ）で精製し、２−エチル−４−メチルピリジン−３−アミンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ｐｐｍ ７．９２ （ｄ、Ｊ＝５．０ Ｈｚ、１ Ｈ）、６．８７ （ｄ、Ｊ＝４．８ Ｈｚ、１ Ｈ）、３．５９ （ｂｒ ｓ、２ Ｈ）、２．７４ （ｑ、Ｊ＝７．６ Ｈｚ、２ Ｈ）、２．１９ （ｓ、３ Ｈ）、１．３３ （ｔ、Ｊ＝７．６ Ｈｚ、３ Ｈ）。ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： １３７．１ （Ｍ＋Ｈ）^＋。 Example 46
6-Chloro-1- (2-ethyl-4-methyl-3-pyrimidine) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1- Piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on.

Step 1: 2-Ethyl-4-methylpyridine-3-amine (Intermediate W).
Ethylmagnesium bromide (3M diethyl ether solution, 3.5 mL, 10.5 mmol) was slowly added to the zinc chloride solution (0.5 M THF solution, 18 mL, 9.0 mmol) with a syringe. The addition was exothermic. The solution is stirred at room temperature for 10 minutes, followed by 3-amino-2-bromo-4-picoline (1.5 g, 8.0 mmol, Combi-Blocks, San Diego, CA, USA) and dichloromethane [1,1'-. Bis (diphenylphosphino) ferrocene] dichlorolide palladium (ii) dichloromethane adduct (120 mg, 0.16 mmol) was added. The resulting mixture was heated at 50 ° C. for 20 minutes, then the heating was stopped and the reaction was cooled to room temperature. The reaction of the reaction mixture was stopped with 10% ammonium hydroxide solution (30 mL) and extracted with EtOAc (80 mL, then 40 mL twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 1-5% / DCM) to give 2-ethyl-4-methylpyridine-3-amine. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 7.92 (d, J = 5.0 Hz, 1 H), 6.87 (d, J = 4.8 Hz, 1 H), 3.59 (Br s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H) ). m / z (ESI, + ve ion): 137.1 (M + H) ⁺ .

Step 2: 2,5,6-trichloro-N-((2-ethyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide.
Slowly add oxalyl chloride (2M DCM solution, 5.4 mL, 10.8 mmol) to a THF solution (20 mL) of 2,5,6-trichloronicotinamide (intermediate P, 2.5 g, 11.1 mmol) with a syringe. It was. The resulting mixture was heated at 65 ° C. for 1.5 hours, then the heating was stopped and the reaction was cooled to room temperature. A solution of 2-ethyl-4-methylpyridine-3-amine (Intermediate W, 1.5 g, 10.7 mmol) in THF (15 mL) was added by cannula. The resulting mixture was stirred at room temperature for 1 hour and then partially concentrated to remove most THF. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution (30 mL) and EtOAc (50 mL). The organic layer was washed with brine (once), dried over anhydrous sodium sulfate and concentrated. The residue is suspended in heptane / EtOAc (10: 1) (60 mL), filtered and 2,5,6-trichloro-N-((2-ethyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide. Got The product was used directly in the next step.

Step 3: 6,7-Dichloro-1- (2-ethyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF solution) in ice-cooled THF solution (60 mL) of 2,5,6-trichloro-N-((2-ethyl-4-methylpyridine-3-yl) carbamoyl) nicotinamide (10.7 mmol), 16.0 mL, 16.0 mmol) was added slowly with a syringe. The resulting solution was stirred at 0 ° C. for 10 minutes, then the reaction was stopped with saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (60 mL). The organic layer was washed with brine (once), dried over anhydrous sodium sulfate and concentrated. The residue is suspended in heptane / EtOAc (9: 1) (60 mL), filtered and 6,7-dichloro-1- (2-ethyl-4-methylpyridine-3-yl) pyrido [2,3-d ] Pyrimidine-2,4 (1H, 3H) -dione was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.14-12.39 (m, 1 H), 8.54 (s, 1 H), 8.47 (d, J = 5.0 Hz) , 1H), 7.28 (d, J = 5.0 Hz, 1H), 2.41-2.49 (m, 2H), 2.03 (s, 3H), 1.07 ( t, J = 7.5 Hz, 3H). m / z (ESI, + ve ion): 350.9 (M + H) ⁺ .

Step 4: 4- (6,7-dichloro-1- (2-ethyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl ) -3-Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
6,7-Dichloro-1- (2-ethyl-4-methylpyridine-3-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (1.0 g, 2.9 mmol) ) And DIPEA (1.5 mL, 8.6 mmol) in acetonitrile (8 mL) was added phosphorus oxychloride (0.40 mL, 4.3 mmol). The resulting solution was heated at 80 ° C. for 30 minutes and then cooled to 0 ° C. DIPEA (1.5 mL, 8.6 mmol) was then added (S) -4-N-Boc-2-methylpiperazine (800 mg, 4.0 mmol, Combi-Blocks, Inc., San Diego, CA, USA). .. The resulting mixture was warmed to room temperature, stirred for 30 minutes, diluted with EtOAc (30 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 10-50% / heptane) and 4- (6,7-dichloro-1- (2-ethyl-4-methylpyridine-3). -Il) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.46 (d, J = 5.0 Hz, 1 H), 8.44 (s, 1 H), 7.27 (d, J = 5) .0 Hz, 1 H), 4.85 (br s, 1 H), 4.12-4.21 (m, 1 H), 3.95 (br s, 1 H), 3.82 (br d) , J = 12.9 Hz, 1H), 3.69 (br d, J = 11.4 Hz, 1H), 2.94-3.27 (m, 2H), 2.25-2. 43 (m, 2H), 1.94 (d, J = 1.7 Hz, 3H), 1.45 (s, 9H), 1.32 (t, J = 6.2 Hz, 3H) ), 1.05 (t, J = 7.6 Hz, 3 H). m / z (ESI, + ve ion): 533.0 (M + H) ⁺ .

Step 5: 4- (6-chloro-1- (2-ethyl-4-methylpyridine-3-yl) -7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3- d] Pyrimidine-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl.
4- (6,7-dichloro-1- (2-ethyl-4-methylpyridine-3-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3 -Methylpiperazin-1-carboxylic acid (S) -tert-butyl (450 mg, 0.84 mmol), (2-fluorophenyl) boronic acid (199 mg, 1.43 mmol, Combi-Blocks, San Diego, CA, USA), 1,4-Dioxane in which a mixture of potassium acetate (250 mg, 2.55 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (33 mg, 0.04 mmol) was dissolved. The mixture of the solution (5 mL) and water (1 mL) was degassed with nitrogen and heated at 65 ° C. for 1.5 hours. The reaction was cooled to room temperature, then diluted with EtOAc (40 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 10-50% / heptane) and 4- (6-chloro-1- (2-ethyl-4-methylpyridine-3-yl). ) -7- (2-Fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl Got ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.43 (s, 1 H), 8.36 (d, J = 5.0 Hz, 1 H), 7.47-7.55 (m) , 1H), 7.20-7.33 (m, 4H), 4.90 (br s, 1H), 4.24 (br s, 1H), 3.99 (br s, 1H) ), 3.85 (br d, J = 13.3 Hz, 1 H), 3.72 (br d, J = 11.6 Hz, 1 H), 3.33-3.47 (m, 1 H) ), 3.03-3.21 (m, 1H), 2.30-1.43 (m, 2H), 1.95 (s, 3H), 1.46 (s, 9H), 1.36 (t, J = 6.1 Hz, 3H), 1.04 (dt, J = 7.5, 2.3 Hz, 3H). ¹⁹ F NMR (377 MHz, chloroform-d) δ ppm −113.84 − −113.85 (2s, 1F). m / z (ESI, + ve ion): 592.9 (M + H) ⁺ .

Step 6: 6-Chloro-1- (2-ethyl-4-methyl-3-pyrimidine) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl)) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
Trifluoroacetic acid (3.0 mL, 40.3 mmol), 4- (6-chloro-1- (2-ethyl-4-methylpyridine-3-yl) -7- (2-fluorophenyl) -2-oxo -1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl (500 mg, 0.84 mmol) in DCM solution (10 mL) added. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in DCM (10 mL) and treated with DIPEA (0.500 mL, 2.86 mmol) followed by acryloyl chloride (0.100 mL, 1.23 mmol) in DCM solution (2 mL). The reaction was stirred at room temperature for 30 minutes, after which the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saline (5 mL). The mixture was extracted with EtOAc (15 mL, twice) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 10-60% / heptane) and 6-chloro-1- (2-ethyl-4-methyl-3-pyridinyl) -7-. (2-Fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.45 (d, J = 5.0 Hz, 1 H), 8.10 (s, 1 H), 7.38-7.46 (m, 1 H), 7.08-7.20 (m, 4 H), 6.62 (br s, 1 H), 6.42 (dd, J = 16.7, 1.6 Hz, 1 H), 5.82 (dd, J = 10.5, 1.8 Hz, 1 H), 4.24-5.21 (m, 3 H), 3.60-4.15 (m, 3 H), 3 .00-3.36 (m, 1H), 2.41-2.60 (m, 2H), 2.00-2.12 (m, 3H), 1.45-1.61 (m) 3, 3 H), 1.15-122 (m, 3 H). ¹⁹ F NMR (377 MHz, chloroform-d) δ ppm −111.94 − −113.08 (m, 1 F). m / z (ESI, + ve ion): 547.2 (M + H) ⁺ .

ステップ１：４，６−ジビニルピリミジン−５−アミン。
４，６−ジクロロ−５−アミノピリミジン（５．０ｇ、３０．５ｍｍｏｌ、Ｓｉｇｍａ Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ）、カリウムビニルトリフルオロボラート（１６．３ｇ、１２２ｍｍｏｌ、Ｓｉｇｍａ Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ）、Ｐｄ（ｄｐｐｆ）Ｃｌ_２（１．１２ｇ、１．５２ｍｍｏｌ）、炭酸セシウム（４９．７ｇ、１５２ｍｍｏｌ）の混合物を溶解させた１，４−ジオキサン溶液（１３０ｍＬ）と水（１３ｍＬ）との混合液を窒素で脱気し、１００℃で４時間加熱した。反応物を室温に冷却し、その後、水で希釈し、ＥｔＯＡｃ（１００ｍＬ、３回）、ＤＣＭ（１００ｍＬ、５回）で順に抽出した。合わせた有機層を無水硫酸マグネシウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＤＣＭ−ＭｅＯＨ（４：１）０〜２０％／ＤＣＭ）で精製し、４，６−ジビニルピリミジン−５−アミンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ｐｐｍ ８．６２ （ｓ、１ Ｈ）、６．８０−６．８９ （ｍ、２ Ｈ）、６．４６ （ｄｄ、Ｊ ＝ １７．０、１．７ Ｈｚ、２ Ｈ）、５．７１ （ｄｄ、Ｊ ＝ １０．９、１．８ Ｈｚ、２ Ｈ）、３．８６ （ｂｒ ｓ、２ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ ｖｅ イオン）： １４８．１ （Ｍ＋Ｈ）^＋。 Example 47
6-Chloro-1- (4,6-diethyl-5-pyrimidinenyl) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) Pyrimidine [2,3-d] Pyrimidine-2 (1H) -on

Step 1: 4,6-Divinylpyrimidine-5-amine.
4,6-dichloro-5-aminopyrimidine (5.0 g, 30.5 mmol, Sigma Aldrich, St. Louis, MO), potassium vinyl trifluoroborate (16.3 g, 122 mmol, Sigma Aldrich, St. Louis, MO) , Pd (dpppf) Cl ₂ (1.12 g, 1.52 mmol), cesium carbonate (49.7 g, 152 mmol) dissolved in a mixture of 1,4-dioxane solution (130 mL) and water (13 mL). Was degassed with nitrogen and heated at 100 ° C. for 4 hours. The reaction was cooled to room temperature, then diluted with water and extracted sequentially with EtOAc (100 mL, 3 times) and DCM (100 mL, 5 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM-MeOH (4: 1) 0-20% / DCM) to give 4,6-divinylpyrimidine-5-amine. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.62 (s, 1 H), 6.80-6.89 (m, 2 H), 6.46 (dd, J = 17.0, 1) .7 Hz, 2 H), 5.71 (dd, J = 10.9, 1.8 Hz, 2 H), 3.86 (br s, 2 H). m / z (ESI, + ve ion): 148.1 (M + H) ⁺ .

Step 2: 4,6-diethylpyrimidine-5-amine (Intermediate X).
An ethanol solution (50 mL) of 4,6-divinylpyrimidine-5-amine (3.1 g, 21.1 mmol) was treated with palladium (10 wt% activated charcoal, 1.12 g, 1.05 mmol). The mixture was purged with 20 psi hydrogen (4 times) and stirred under 20 psi hydrogen at room temperature for 4 hours. The reaction mixture was filtered through a Celite pad and concentrated to give 4,6-diethylpyrimidine-5-amine. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.59 (s, 1 H), 3.62 (br s, 2 H), 2.70 (q, J = 7.6 Hz, 4 H) , 1.34 (t, J = 7.6 Hz, 6 H). m / z (ESI, + ve ion): 152.2 (M + H) ⁺ .

Step 3: 2,5,6-trichloro-N-((4,6-diethylpyrimidine-5-yl) carbamoyl) nicotinamide.
Oxalyl chloride (2M DCM solution, 15.5 mL, 31.0 mmol) was added to a THF suspension (100 mL) of 2,5,6-trichloronicotinamide (Intermediate P, 4.67 g, 20.7 mmol). The resulting mixture was heated at 65 ° C. for 1 hour, then the heating was stopped and the reactants were concentrated to one-third the volume. Toluene (100 mL) was added and the mixture was cooled to 0 ° C. A solution of 1,6-dichloroethane (20 mL) of 4,6-diethylpyrimidine-5-amine (Intermediate X, 3.13 g, 20.7 mmol) was added dropwise by cannula. The resulting mixture was warmed to room temperature, stirred for 15 minutes and then concentrated. The residue was suspended in MTBE (50 mL) and filtered. The filtered solid was dried in a vacuum oven at 50 ° C. for a short time to obtain 2,5,6-trichloro-N-((4,6-diethylpyrimidine-5-yl) carbamoyl) nicotinamide. m / z (ESI, + ve ion): 402.1 (M + H) ⁺ .

Step 4: 6,7-Dichloro-1- (4,6-diethylpyrimidine-5-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF) in ice-cold THF solution (100 mL) of 2,5,6-trichloro-N-((4,6-diethylpyrimidine-5-yl) carbamoyl) nicotinamide (7.28 g, 18.1 mmol) The solution, 36.2 mL, 36.2 mmol) was added slowly with a syringe. The resulting mixture was warmed to room temperature and stirred for 5 minutes, after which the reaction was stopped with saturated aqueous ammonium chloride solution and extracted with EtOAc (100 mL, 5 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was dried in a vacuum oven at 45 ° C. overnight and 6,7-dichloro-1- (4,6-diethylpyrimidine-5-yl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -Zeon was obtained. This material was used in subsequent steps without further purification. m / z (ESI, + ve ion): 366.0 (M + H) ⁺ .

Step 5: 4- (6,7-dichloro-1- (4,6-diethylpyrimidine-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl)- 3-Methylpiperazine-1-carboxylic acid (S) -tert-butyl.

6,7-Dichloro-1- (4,6-diethylpyrimidine-5-yl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (3.87 g, 10.6 mmol) Acetonitrile solution (30 mL) was treated with triethylamine (3.71 mL, 26.4 mmol) followed by phosphorus oxychloride (1.26 mL, 12.7 mmol). The resulting mixture was heated at 60 ° C. for 30 minutes and then cooled to 0 ° C. Triethylamine (1.50 mL, 10.7 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (2.22 g, 11.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA). added. The reaction mixture was warmed to room temperature, stirred for 30 minutes and then partitioned between EtOAc (100 mL) and saline (40 mL). The organic layer was washed with water (30 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-100% / heptane) and 4- (6,7-dichloro-1- (4,6-diethylpyrimidine-5-yl) -2-oxo-1, 2-Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.09 (s, 1 H), 8.48 (s, 1 H), 4.88 (br s, 1 H), 4.19 (br) d, J = 13.7 Hz, 1 H) 3.90-4.00 (m, 1 H), 3.83 (br d, J = 13.7 Hz, 1 H) 3.66-3 .78 (m, 1H), 3.05-3.35 (m, 2H), 2.35-2.46 (m, 4H), 1.45 (s, 9H), 1.33 (D, J = 6.6 Hz, 3 H), 1.08 (t, J = 7.5 Hz, 6 H). m / z (ESI, + ve ion): 548.2 (M + H) ⁺ .

Step 6: 4- (6-chloro-1- (4,6-diethylpyrimidine-5-yl) -7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4- (6,7-dichloro-1- (4,6-diethylpyrimidine-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methyl Piperazin-1-carboxylic acid (S) -tert-butyl (354 mg, 0.65 mmol), (2-fluorophenyl) boronic acid (108 mg, 0.78 mmol, Combi-Blocks, San Diego, CA, USA), potassium acetate A 1,4-dioxane solution (6.5 mL) of a mixture of (317 mg, 3.23 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (23 mg, 0.03 mmol). ) Was degassed with argon for 5 minutes. 4 drops of water were added and the mixture was heated at 90 ° C. for 30 minutes. The reaction was cooled to room temperature and then partitioned with water (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM-MeOH (4: 1) 0-30% / DCM) and 4- (6-chloro-1- (4,6-diethylpyrimidine-5-yl)-. Obtained 7- (2-fluorophenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl It was. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.01 (s, 1 H), 8.45 (s, 1 H), 7.49-7.57 (m, 1 H), 7. 26-7.34 (m, 2H), 7.20-7.26 (m, 1H), 4.88-4.98 (m, 1H), 4.27 (br d, J = 13. 7 Hz, 1 H), 3.93-4.03 (m, 1 H), 3.85 (br d, J = 13.5 Hz, 1 H), 3.70-3.81 (m, 1) H), 3.05-3.35 (m, 2H), 2.35-2.46 (m, 4H), 1.46 (s, 9H), 1.37 (d, J = 6) .6 Hz, 3 H), 1.06 (td, J = 7.5, 1.6 Hz, 6 H). m ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ ppm -114.01 (s, 1 F). m / z (ESI, + ve ion): 608.2 (M + H) ⁺ .

Step 7: 6-Chloro-1- (4,6-diethyl-5-pyrimidineyl) -7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1 -Piperadinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on.
Trifluoroacetic acid (3.0 mL, 38.9 mmol), 4- (6-chloro-1- (4,6-diethylpyrimidine-5-yl) -7- (2-fluorophenyl) -2-oxo-1 , 2-Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (S) -tert-butyl (327 mg, 0.54 mmol) added to a DCM solution (5 mL). .. The resulting mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was dissolved in DCM (10 mL), cooled to 0 ° C. and treated with DIPEA (0.470 mL, 2.69 mmol) followed by acryloyl chloride (0.048 mL, 0.59 mmol). The reaction was stirred at 0 ° C. for 10 minutes, after which additional DIPEA (0.300 mL, 1.71 mmol) was added, followed by additional acryloyl chloride (0.020 mL, 0.25 mmol). After 20 minutes at 0 ° C., the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with DCM (30 mL, twice). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: DCM-MeOH (4: 1) 0-60% / DCM) and 6-chloro-1- (4,6-diethyl-5-pyrimidinyl) -7- (2). -Fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -one was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.01 (s, 1 H), 8.48 (br d, J = 5.0 Hz, 1 H), 7.50-7.57 ( m, 1H), 7.27-7.35 (m, 3H), 7.20-7.27 (m, 1H), 6.79-6.93 (m, 1H), 6. 17-6.26 (m, 1H), 5.65-5.80 (m, 1H), 4.92-5.02 (m, 1H), 4.23-4.44 (m, 2H) 3.99-4.20 (m, 1H) 3.72-3.88 (m, 1H) 3.40-3.71 (m, 1H) 2.35- 2.48 (m, 4H), 1.36 (d, J = 6.6 Hz, 3H), 1.06 (t, J = 7.5 Hz, 6H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ ppm -114.01 (s, 1 F). m / z (ESI, + ve ion): 562.1 (M + H) ⁺ .

ステップ１：２，５，６−トリクロロ−Ｎ−（（４−イソプロピルチアゾール−５−イル）カルバモイル）ニコチンアミド。
２，５，６−トリクロロニコチンアミド（中間体Ｐ、１．００ｇ、４．５ｍｍｏｌ）の混合ＴＨＦ溶液（２０ｍＬ）に塩化オキサリル（２Ｍ ＤＣＭ溶液、２．４ｍＬ、４．９ｍｍｏｌ）を加えた。得られた混合物を７０℃で３０分間加熱し、その後、加熱を中止し、反応物を室温に冷却した。４−（プロパン−２−イル）−１，３−チアゾール−５−アミン（７１５ｍｇ、５．０ｍｍｏｌ、Ｅｎａｍｉｎｅ、Ｍｏｎｍｏｕｔｈ Ｊｕｎｃｔｉｏｎ、ＮＪ、ＵＳＡ）を加えた。反応混合物を室温で１０分間撹拌し、その後、濃縮した。残渣をＭｅＯＨに懸濁させ、ろ過した。ろ過後の固形物を捨て、ろ液を濃縮し、２，５，６−トリクロロ−Ｎ−（（４−イソプロピルチアゾール−５−イル）カルバモイル）ニコチンアミドを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ １１．６９ （ｂｒ ｓ、１ Ｈ）、１０．６４ （ｂｒ ｓ、１ Ｈ）、８．７１ （ｓ、１ Ｈ）、８．５８ （ｓ、１ Ｈ）、３．１３ （ｂｒ ｄ、Ｊ ＝ ６．４ Ｈｚ、１ Ｈ）、１．２５ （ｄ、Ｊ ＝ ６．８ Ｈｚ、６ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ ｖｅ イオン）： ３９３．０ （Ｍ＋Ｈ）^＋。 Example 48
6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (4- (2-propanil) ) -1,3-Thiazole-5-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one

Step 1: 2,5,6-trichloro-N-((4-isopropylthiazole-5-yl) carbamoyl) nicotinamide.
Oxalyl chloride (2M DCM solution, 2.4 mL, 4.9 mmol) was added to a mixed THF solution (20 mL) of 2,5,6-trichloronicotinamide (intermediate P, 1.00 g, 4.5 mmol). The resulting mixture was heated at 70 ° C. for 30 minutes, then the heating was stopped and the reaction was cooled to room temperature. 4- (Propan-2-yl) -1,3-thiazole-5-amine (715 mg, 5.0 mmol, Enamine, Monmouth Junction, NJ, USA) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was suspended in MeOH and filtered. The solid matter after filtration was discarded, and the filtrate was concentrated to obtain 2,5,6-trichloro-N-((4-isopropylthiazole-5-yl) carbamoyl) nicotinamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.69 (br s, 1 H), 10.64 (br s, 1 H), 8.71 (s, 1 H), 8.58 ( s, 1 H), 3.13 (br d, J = 6.4 Hz, 1 H), 1.25 (d, J = 6.8 Hz, 6 H). m / z (ESI, + ve ion): 393.0 (M + H) ⁺ .

Step 2: 6,7-Dichloro-1- (4-isopropylthiazole-5-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF solution) in ice-cooled THF solution (20 mL) of 2,5,6-trichloro-N-((4-isopropylthiazole-5-yl) carbamoyl) nicotinamide (1.75 g, 4.5 mmol), 9.3 mL, 9.3 mmol) was added. The resulting mixture was warmed to room temperature, stirred for 30 minutes, recooled to 0 ° C. and treated with KHMDS (1M THF solution, 1.0 mL, 1.0 mmol). After warming the reaction to room temperature and stirring for 15 minutes, the reaction was stopped with semi-saturated aqueous ammonium chloride solution (60 mL) and extracted with EtOAc (50 mL, twice). The combined organic layers were washed with water (60 mL) and dried and concentrated by elution through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA). The residue was purified by silica gel chromatography (eluent: EtOAc 5-70% / heptane) and 6,7-dichloro-1- (4-isopropylthiazole-5-yl) pyrido [2,3-d] pyrimidin-2, 4 (1H, 3H) -dione was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.20 (s, 1 H), 9.14 (s, 1 H), 8.54 (s, 1 H), 2.86 (quin, J = 6.8 Hz, 1 H), 1.11 (t, J = 7.4 Hz, 6 H). m / z (ESI, + ve ion): 357.0 (M + H) ⁺ .

Step 3: 4- (6,7-dichloro-1- (4-isopropylthiazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3- Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
Mixed acetonitrile of 6,7-dichloro-1- (4-isopropylthiazole-5-yl) pyrido [2,3-d] pyrimidin-2,4 (1H, 3H) -dione (3.01 g, 8.4 mmol) DIPEA (4.40 mL, 25.3 mmol) followed by phosphorus oxychloride (1.57 mL, 16.8 mmol) was added to the solution (40 mL). The resulting mixture was heated at 80 ° C. for 15 minutes, then cooled to room temperature and concentrated. The residue was dissolved in DMF (30 mL), DIPEA (7.34 mL, 42.2 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (1.89 g, 9.5 mmol, Sigma-Aldrich, St. .Louis, MO, USA). The resulting solution was stirred at room temperature for 5 minutes, then ice water (100 mL) was added and the mixture was stirred for an additional 15 minutes. The mixture was filtered off and the filtered solid was dissolved in DCM, passed through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA), dried and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 40-100% / heptane) and 4- (6,7-dichloro-1- (4-isopropylthiazole-5-yl) -2-oxo-1,2-yl). Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.10 (s, 1 H), 8.40 (d, J = 1.7 Hz, 1 H), 4.85 (br s, 1 H) ), 4.07-4.18 (m, 1H), 3.88-4.00 (m, 1H), 3.81 (br d, J = 13.9 Hz, 1H), 3. 64-3.77 (m, 1H), 3.28 (s, 1H), 3.01-3.19 (m, 1H,), 2.65 (t, J = 13.3, 6) .6 Hz, 1 H), 1.44 (s, 9 H), 1.31 (dd, J = 6.4, 3.3 Hz, 3 H), 1.09-1.13 (m, 6) H). m / z (ESI, + ve ion): 539.2 (M + H) ⁺ .

Step 4: 4- (6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (4-isopropylthiazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3- d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (6,7-dichloro-1- (4-isopropylthiazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin- 1-Carboxylic acid (S) -tert-butyl (2.03 g, 3.76 mmol), potassium acetate (1.86 g, 18.9 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (911 mg, 5. 1,4 of a mixture of 84 mmol, Combi-Blocks, San Diego, CA, USA), and [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) dichloromethane complex (282 mg, 0.39 mmol) -Dichloromethane solution (36 mL) was degassed with argon for 5 minutes. One drop of water was added and the resulting mixture was heated to 90 ° C. for 1.5 hours. The reaction was cooled to room temperature and then partitioned between water (50 mL) and EtOAc (50 mL, twice). The combined organic extracts were washed with water (60 mL) and dried and concentrated by elution through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA). The residue was purified by silica gel chromatography (eluent: EtOAc 50-100% / heptane) and 4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (4-isopropylthiazole-5-). Il) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.10 (s, 1 H), 9.00 (s, 1 H), 8.31-8.39 (m, 1 H), 7. 21-7.32 (m, 1H), 6.65-6.77 (m, 2H), 4.88 (br s, 1H), 4.11-4.33 (m, 1H) 3.91-3.98 (m, 1H), 3.83 (br d, J = 13.9 Hz, 1H), 3.64-3.78 (m, 1H), 3.28 (Br s, 1 H), 3.03-3.21 (m, 1 H), 2.63 (br s, 1 H), 1.45 (s, 9 H), 1.36 (br s, 3 H), 1.09 (br d, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -115.41 (br s, 1 F). m / z (ESI, + ve ion): 615.2 (M + H) ⁺ .

Step 5: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (4- ( 2-Propanil) -1,3-thiazole-5-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
Trifluoroacetic acid (10 mL, 130 mmol), 4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (4-isopropylthiazole-5-yl) -2-oxo-1,2 -Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl (2.15 g, 3.50 mmol) was added to a DCM solution (20 mL). .. The reaction was stirred for 30 minutes at room temperature and then concentrated. The residue was dissolved in DCM (20 mL), cooled to 0 ° C. and treated with DIPEA (3.05 mL, 17.5 mmol) followed by acryloyl chloride solution (0.258 M DCM solution, 10.84 mL, 2.8 mmol). The reaction mixture was warmed to room temperature, stirred for 15 minutes, recooled to 0 ° C. and treated with acryloyl chloride solution (0.258 M DCM solution, 2.0 mL, 0.52 mmol). After raising the temperature to room temperature, the mixture was further stirred for 10 minutes to concentrate the reaction product. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 40-100% / heptane) and 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -4-((2S). ) -2-Methyl-4- (2-propenoyl) -1-piperazinyl) -1- (4- (2-propanol) -1,3-thiazole-5-yl) pyrido [2,3-d] pyrimidine- 2 (1H) -on was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.10 (s, 1 H), 9.01 (s, 1 H), 8.37 (br s, 1 H), 7.22-7 .32 (m, 1H), 6.80-6.93 (m, 1H), 6.66-6.77 (m, 2H), 6.20 (br d, J = 16.6 Hz) , 1H), 5.71-5.81 (m, 1H), 4.83-5.04 (m, 1H), 3.98-4.45 (m, 3H), 3.56 -3.87 (m, 2H), 3.07 (br dd, J = 4.1, 2.9 Hz, 1H), 2.59-2.70 (m, 1H), 1.33 (Br d, J = 5.8 Hz, 3 H), 1.07-1.14 (m, 3 H), 1.01 (br d, J = 6.6 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -115.41 (br s, 1 F). m / z (ESI, + ve ion): 569.2 (M + H) ⁺ .

ステップ１：Ｎ−（（２−（ｔｅｒｔ−ブチル）フェニル）カルバモイル）−２，５，６−トリクロロニコチンアミド。
２，５，６−トリクロロニコチンアミド（中間体Ｐ、１．０２ｇ、４．５ｍｍｏｌ）の混合ＴＨＦ溶液（２０ｍＬ）に塩化オキサリル（２Ｍ ＤＣＭ溶液、２．５ｍＬ、５．０ｍｍｏｌ）を加えた。得られた混合物を７０℃で４０分間加熱し、その後、加熱を中止し、反応物を室温に冷却した。２−ｔｅｒｔ−ブチルアニリン（０．７０８ｍＬ、４．５ｍｍｏｌ、Ａｒｋ Ｐｈａｒｍ、Ａｒｌｉｎｇｔｏｎ Ｈｅｉｇｈｔｓ、ＩＬ、ＵＳＡ）を加えた。反応混合物を室温で１０分間撹拌し、その後、濃縮した。残渣をＭｅＯＨに懸濁させ、ろ過した。ろ過後の固形物を回収し、Ｎ−（（２−（ｔｅｒｔ−ブチル）フェニル）カルバモイル）−２，５，６−トリクロロニコチンアミドを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ １１．４３ （ｂｒ ｓ、１ Ｈ）、９．７９−１０．１６ （ｍ、１ Ｈ）、８．６５ （ｓ、１ Ｈ）、７．４９ （ｂｒ ｄｄ、Ｊ ＝ ７．５、１．７ Ｈｚ、１ Ｈ）、７．４３ （ｂｒ ｄ、Ｊ ＝ ７．７ Ｈｚ、１ Ｈ）、７．１８−７．２８ （ｍ、２ Ｈ）、１．４０ （ｓ、９ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ ｖｅ イオン）： ４２２．０ （Ｍ＋Ｎａ）^＋。 Example 49
6-Chloro-7- (2-Fluoro-6-Hydroxyphenyl) -1- (2- (2-Methyl-2-propanil) Phenyl) -4-((2S) -2-Methyl-4- (2-) Propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: N-((2- (tert-butyl) phenyl) carbamoyl) -2,5,6-trichloronicotinamide.
Oxalyl chloride (2M DCM solution, 2.5 mL, 5.0 mmol) was added to a mixed THF solution (20 mL) of 2,5,6-trichloronicotinamide (intermediate P, 1.02 g, 4.5 mmol). The resulting mixture was heated at 70 ° C. for 40 minutes, then the heating was stopped and the reaction was cooled to room temperature. 2-tert-Butylaniline (0.708 mL, 4.5 mmol, Ark Pharma, Arlington Heights, IL, USA) was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated. The residue was suspended in MeOH and filtered. The solid matter after filtration was recovered to obtain N-((2- (tert-butyl) phenyl) carbamoyl) -2,5,6-trichloronicotinamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.43 (br s, 1 H), 9.79-10.16 (m, 1 H), 8.65 (s, 1 H), 7 .49 (br dd, J = 7.5, 1.7 Hz, 1 H), 7.43 (br d, J = 7.7 Hz, 1 H), 7.18-7.28 (m, 2) H), 1.40 (s, 9 H). m / z (ESI, + ve ion): 422.0 (M + Na) ⁺ .

Step 2: 1- (2- (tert-butyl) phenyl) -6,7-dichloropyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF solution) in ice-cooled mixed THF solution (20 mL) of N-((2- (tert-butyl) phenyl) carbamoyl) -2,5,6-trichloronicotinamide (1.26 g, 3.1 mmol) , 6.6 mL, 6.6 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 10 minutes, then semisaturated aqueous ammonium chloride solution (60 mL) was added to stop the reaction and extracted with EtOAc (50 mL twice). The combined organic layers were washed with water (60 mL) and dried and concentrated by elution through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA). The residue was suspended in MeOH and filtered. The solid matter after filtration was recovered to obtain 1- (2- (tert-butyl) phenyl) -6,7-dichloropyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.19 (s, 1 H), 8.56 (s, 1 H), 7.65 (dd, J = 8.2, 1.3 Hz) , 1 H), 7.41-7.46 (m, 1 H), 7.33 (td, J = 7.5, 1.2 Hz, 1 H), 7.21 (dd, J = 7. 8, 1.3 Hz, 1 H), 1.17 (s, 9 H). m / z (ESI, + ve ion): 364.0 (M + H) ⁺ .

Step 3: 4- (1- (2- (tert-butyl) phenyl) -6,7-dichloro-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3- Methylpiperazine-1-carboxylic acid (S) -tert-butyl.
1- (2- (tert-Butyl) phenyl) -6,7-dichloropyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (925 mg, 2.54 mmol) mixed acetonitrile solution (20 mL) ), Then phosphorus oxychloride (0.284 mL, 3.05 mmol) was added after DIPEA (0.574 mL, 3.30 mmol). The resulting mixture was heated at 80 ° C. for 45 minutes and then cooled to 0 ° C. DIPEA (1.33 mL, 7.62 mmol) was then added (S) -4-N-Boc-2-methylpiperazine (0.522 g, 2.61 mmol, Sigma-Aldrich, St. Louis, MO, USA). .. The obtained solution was gradually warmed to room temperature over 40 minutes, poured into a saturated aqueous sodium hydrogen carbonate solution (50 mL), and stirred for another 10 minutes. The mixture was extracted with EtOAc (30 mL, twice) and the combined organic extracts were dried and concentrated by elution through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA). The residue was purified by silica gel chromatography (eluent: EtOAc 30-80% / heptane) and 4- (1- (2- (tert-butyl) phenyl) -6,7-dichloro-2-oxo-1,2- Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.33-8.48 (m, 1 H), 7.61 (d, J = 7.9 Hz, 1 H), 7.36-7 .42 (m, 1H), 7.29 (td, J = 7.5, 1.2 Hz, 1H), 7.00 (dd, J = 7.7, 1.0 Hz, 1H) 4.68-4.89 (m, 1H), 3.88-4.25 (m, 2H), 3.77-3.86 (m, 1H), 3.52-3.71 (M, 1H), 3.09-3.26 (m, 1H), 2.84-3.07 (m, 1H), 1.44 (s, 9H), 1.24 (s) , 3 H), 1.13 (d, J = 2.3 Hz, 9 H). m / z (ESI, + ve ion): 546.2 (M + H) ⁺ .

Step 4: 4- (1- (2- (tert-butyl) phenyl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -2-oxo-1,2-dihydropyride [2,3- d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylic acid (3S) -tert-butyl.
4- (1- (2- (tert-butyl) phenyl) -6,7-dichloro-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin- 1-Carboxylic acid (S) -tert-butyl (1.00 g, 1.83 mmol), potassium acetate (905 mg, 9.22 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (347 mg, 2.22 mmol,, 1,4-Dioxane, a mixture of Combi-Blocks, San Diego, CA, USA) and [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) dichloromethane complex (137 mg, 0.19 mmol) The solution (20 mL) was degassed with argon for 5 minutes. One drop of water was added and the resulting mixture was heated to 90 ° C. for 1.5 hours. The reaction was cooled to room temperature and then partitioned with water (40 mL) and EtOAc (40 mL, twice). The combined organic extracts were washed with water (40 mL), dried by elution through a Chem Elut extraction cartridge (Agilent Technologies, Santa Clara, CA) and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 40-100% / heptane) and 4- (1- (2- (tert-butyl) phenyl) -6-chloro-7- (2-fluoro-6-hydroxy). Phenyl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.03-10.09 (m, 1 H), 8.31-8.39 (m, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 7.25-7.32 (m, 1 H), 7.18-7.24 (m, 2 H), 6.94 (br d, J = 6.6 Hz) , 1H), 6.61-6.73 (m, 2H), 4.80 (br d, J = 1.2 Hz, 1H), 4.09-4.25 (m, 1H) 3.92-4.01 (m, 1H), 3.84 (br d, J = 12.9 Hz, 1 H), 3.63 (br d, J = 9.1 Hz, 1 H) 2.99-3.26 (m, 2H), 1.45 (s, 9H), 1.29-1.37 (m, 3H), 1.11 (s, 9H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm −115.35 − −115.44 (m, 1 F). m / z (ESI, + ve ion): 622.2 (M + H) ⁺ .

Step 5: 6-Chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2- (2-methyl-2-propanil) phenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
Trifluoroacetic acid (5.0 mL, 64.9 mmol), 4- (1- (2- (tert-butyl) phenyl) -6-chloro-7- (2-fluoro-6-hydroxyphenyl) -2-oxo -1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid (3S) -tert-butyl (984 mg, 1.58 mmol) in DCM solution (10 mL) added. The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in DCM (10 mL), cooled to 0 ° C. and treated with DIPEA (1.38 mL, 7.91 mmol) followed by acryloyl chloride solution (0.258 M DCM solution, 4.90 mL, 1.27 mmol). The reaction mixture was warmed to room temperature, stirred for 30 minutes, recooled to 0 ° C. and treated with acryloyl chloride solution (0.258 M DCM solution, 1.0 mL, 0.26 mmol). After raising the temperature to room temperature, the mixture was further stirred for 5 minutes to concentrate the reaction product. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 40-100% / heptane) and 6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-). (2-Methyl-2-propanol) Phenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H)- Got on. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.06 (br d, J = 5.4 Hz, 1 H), 8.38 (br d, J = 12.2 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 1 H), 7.17-7.32 (m, 3 H), 6.91-7.02 (m, 1 H), 6.83 (br) dd, J = 10.2, 16.4 Hz, 1 H), 6.61-6.74 (m, 2 H), 6.20 (br d, J = 16.6 Hz, 1 H), 5 .72-5.80 (m, 1H), 4.85 (br d, J = 2.1 Hz, 1H), 4.07-4.51 (m, 3H), 3.59-3 .81 (m, 3H), 1.24-1.37 (m, 3H), 1.06-1.13 (m, 9H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -115.42 (m, 1 F). m / z (ESI, + ve ion): 576.2 (M + H) ⁺ .

ステップ１：３−アミノ−６−クロロ−５−（２−フルオロフェニル）ピラジン−２−カルボン酸メチル。
３−アミノ−５，６−ジクロロピラジン−２−カルボン酸メチル（１０．０ｇ、４５ｍｍｏｌ、Ａｒｋ Ｐｈａｒｍ，Ｉｎｃ．、Ａｒｌｉｎｇｔｏｎ Ｈｅｉｇｈｔｓ、ＩＬ）、（２−フルオロフェニル）ボロン酸（６．９３ｇ、４９．５ｍｍｏｌ、Ｃｏｍｂｉ−Ｂｌｏｃｋｓ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）、及び炭酸カリウム（１３．１ｇ、９５ｍｍｏｌ）の混合物を溶解させたＤＭＥ／水の１０：１混合液（２２０ｍＬ）を窒素で５分間脱気し、その後、テトラキス（トリフェニルホスフィン）パラジウム（０）（１．０４ｇ、０．９０ｍｍｏｌ）を加えた。反応混合物を９０℃で１６時間撹拌し、その後、室温に冷却し、ＥｔＯＡｃ（２００ｍＬ）と１Ｎ ＨＣｌ（２００ｍＬ）で分配した。有機層を無水硫酸ナトリウムで乾燥させ、濃縮し、３−アミノ−６−クロロ−５−（２−フルオロフェニル）ピラジン−２−カルボン酸メチルを得た。ｍ／ｚ （ＥＳＩ、＋ｖｅ）： ２８２．１ （Ｍ＋Ｈ）^＋。 Example 50
6-Chloro-7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanil) phenyl)- 2 (1H) -Pteridinone

Step 1: Methyl 3-amino-6-chloro-5- (2-fluorophenyl) pyrazine-2-carboxylate.
Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (10.0 g, 45 mmol, Ark Pharm, Inc., Arlington Heights, IL), (2-fluorophenyl) boric acid (6.93 g, 49. A 10: 1 mixture of DME / water (220 mL) in which a mixture of 5 mmol, Combi-Blocks, San Diego, CA, USA) and potassium carbonate (13.1 g, 95 mmol) was dissolved was degassed with nitrogen for 5 minutes. After that, tetrakis (triphenylphosphine) palladium (0) (1.04 g, 0.90 mmol) was added. The reaction mixture was stirred at 90 ° C. for 16 hours, then cooled to room temperature and partitioned between EtOAc (200 mL) and 1N HCl (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give methyl 3-amino-6-chloro-5- (2-fluorophenyl) pyrazine-2-carboxylate. m / z (ESI, + ve): 282.1 (M + H) ⁺ .

Step 2: Methyl 3,6-dichloro-5- (2-fluorophenyl) pyrazine-2-carboxylate.
Isoamyl nitrite (15.8 mL, 117 mmol) and isoamyl nitrite (15.8 mL, 117 mmol) in a t-BuOH solution (220 mL) of methyl 3-amino-6-chloro-5- (2-fluorophenyl) pyrazine-2-carboxylate (22.0 g, 78 mmol). Copper chloride (12.6 g, 94 mmol) was added. The resulting mixture was stirred at 60 ° C. for 16 hours and then partitioned between water (1 L) and EtOAc (2 L). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-5% / hexane) to give methyl 3,6-dichloro-5- (2-fluorophenyl) pyrazine-2-carboxylate. m / z (ESI, + ve ion): 300.9 (M + H) ⁺ .

Step 3: 3,6-Dichloro-5- (2-fluorophenyl) pyrazine-2-carboxamide.
A solution of ammonium hydroxide (30%, 150 mL, 44.8 mmol) in a THF solution (150 mL) of methyl 3,6-dichloro-5- (2-fluorophenyl) pyrazine-2-carboxylate (13.5 g, 44.8 mmol). ) Was added. The resulting mixture was heated at 50 ° C. for 4 hours, then cooled to room temperature and partitioned with water and EtOAc (500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-30% / hexane) to give 3,6-dichloro-5- (2-fluorophenyl) pyrazine-2-carboxamide. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.32 (br s, 1 H), 8.16 (br s, 1 H), 7.64-7.77 (m, 2 H), 7.41-7.47 (m, 2H). m / z (ESI, + ve): 286.0 (M + H) ⁺ .

Step 4: 3,6-dichloro-5- (2-fluorophenyl) -N-((2-isopropylphenyl) carbamoyl) pyrazine-2-carboxamide.
A mixed DCE solution (15 mL) of 3,6-dichloro-5- (2-fluorophenyl) pyrazine-2-carboxamide (704 mg, 2.46 mmol) and an oxalyl chloride solution (2 M DCM solution, 1.35 mL, 2.71 mmol). ) Was heated at 80 ° C. for 1 hour. The reaction was cooled to room temperature and 2-isopropylaniline (0.35 mL, 2.46 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours and then concentrated. The residue was treated with EtOAc, sonicated and filtered. The solid matter after filtration was recovered to obtain 3,6-dichloro-5- (2-fluorophenyl) -N-((2-isopropylphenyl) carbamoyl) pyrazine-2-carboxamide. m / z (ESI, + ve): 446.8 (M + H) ⁺ .

Step 5: 6-Chloro-7- (2-fluorophenyl) -1- (2-isopropylphenyl) pteridine-2,4 (1H, 3H) -dione (intermediate Y).
KHMDS (1M THF solution, 0.93 mL, 0.93 mmol), 3,6-dichloro-5- (2-fluorophenyl) -N-((2-isopropylphenyl) carbamoyl) pyrazine-2-carboxamide (208 mg, 0.46 mmol) was added to the ice-cooled mixed THF solution (4 mL). The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was partitioned between EtOAc (10 mL) and saturated aqueous ammonium chloride solution (5 mL, twice). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-50% / heptane) and 6-chloro-7- (2-fluorophenyl) -1- (2-isopropylphenyl) pteridine-2,4 (1H, 3H). ) -Obtained Zeon. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.50 (br s, 1 H), 7.40-7.47 (m, 3 H), 7.31 (dt, J = 8.3, 4.2 Hz, 1 H), 7.17-7.24 (m, 2 H), 7.09-7.16 (m, 2 H), 2.69 (quin, J = 6.8 Hz, 1 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H). m / z (ESI, + ve): 410.9 (M + H) ⁺ .

Step 6: 6-Chloro-7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanil)) Phenyl) -2 (1H) -pteridinone.
6-Chloro-7- (2-fluorophenyl) -1- (2-isopropylphenyl) pteridine-2,4 (1H, 3H) -dione (373 mg, 0.91 mmol) in acetonitrile solution (5 mL) with DIPEA ( 0.269 mL, 1.54 mmol) followed by phosphorus oxychloride (0.127 mL, 1.36 mmol). The resulting solution was stirred at 80 ° C. for 30 minutes and then concentrated. The residue was dissolved in DMF (5 mL) and cooled to 0 ° C., followed by DIPEA (0.54 mL, 3.08 mmol) and then (S) -1- (3-methylpiperazin-1-yl) propa-2-ene-. It was treated with a DMF solution (0.5 mL) of 1-on 2,2,2-trifluoroacetate (582 mg, 1.00 mmol). The resulting solution was stirred at 0 ° C. for 30 minutes and then gradually warmed to room temperature. The reaction was partitioned between EtOAc (10 mL) and water (10 mL, twice). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-3% / DCM) and 6-chloro-7- (2-fluorophenyl) -4-((2S) -2-methyl-4- (2-propenoyl). ) -1-Piperadinyl) -1- (2- (2-propanil) phenyl) -2 (1H) -pteridinone was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.51-7.61 (m, 1 H), 7.44 (dt, J = 7.9, 1.9 Hz, 1 H), 7 .33-7.38 (m, 2H), 7.27-7.32 (m, 2H), 7.24 (br t, J = 7.7 Hz, 1 H), 7.13 (br) dt, J = 7.9, 1.7 Hz, 1 H), 6.89 (br dd, J = 16.4, 10.4 Hz, 1 H), 6.22 (br d, J = 16. 4 Hz, 1 H), 5.76 (dd, J = 10.2, 1.2 Hz, 1 H), 4.68-5.54 (m, 1 H), 4.21-4.44 ( m, 6 H) 2.69-2.83 (m, 1 H), 1.21-1.31 (m, 3 H), 1.10 (t, J = 6.3 Hz, 3 H) , 0.99 (dd, J = 6.7, 3.4 Hz, 3H). m / z (ESI, + ve): 546.8 (M + H) ⁺ .

ステップ１：７−（２−フルオロフェニル）−１−（２−イソプロピルフェニル）−６−メチルプテリジン−２，４（１Ｈ，３Ｈ）−ジオン。
ガラス製マイクロ波反応槽に、６−クロロ−７−（２−フルオロフェニル）−１−（２−イソプロピルフェニル）プテリジン−２，４（１Ｈ，３Ｈ）−ジオン（中間体Ｙ、９３０ｍｇ、２．２７ｍｍｏｌ）、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］−ジクロロパラジウム（ＩＩ）ジクロロメタン錯体（１６６ｍｇ、０．２８ｍｍｏｌ）、トリメチルボロキシン（０．６４ｍＬ、４．５４ｍｍｏｌ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ、Ｓｔ．Ｌｏｕｉｓ、ＭＯ、ＵＳＡ）、及び炭酸カリウム（０．６３ｇ、４．５４ｍｍｏｌ）の混合物のジオキサン／水溶液（１０：１）（１１ｍＬ）を投入した。反応物を窒素で５分間脱気し、Ｅｍｒｙｓ Ｏｐｔｉｍｉｚｅｒマイクロ波反応装置（Ｂｉｏｔａｇｅ、Ｕｐｐｓａｌａ、Ｓｗｅｄｅｎ）で１００℃にて１．５時間加熱した。反応物を室温に冷却した後、水（１０ｍＬ）とＥｔＯＡｃ（１０ｍＬ）で分配した。有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残渣をシリカゲルクロマトグラフィー（溶離液：ＥｔＯＡｃ０〜４０％／ヘプタン）で精製し、７−（２−フルオロフェニル）−１−（２−イソプロピルフェニル）−６−メチルプテリジン−２，４（１Ｈ，３Ｈ）−ジオンを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、クロロホルム−ｄ） δ ｐｐｍ ８．５３ （ｂｒ ｓ、１ Ｈ）、７．３８−７．４８ （ｍ、３ Ｈ）、７．３０ （ｄｔ、Ｊ ＝ ８．３、４．２ Ｈｚ、１ Ｈ）、７．０８−７．２０ （ｍ、４ Ｈ）、２．７１ （ｑｕｉｎ、Ｊ ＝ ６．８ Ｈｚ、１ Ｈ）、２．６１ （ｄ、Ｊ ＝ ２．３ Ｈｚ、３ Ｈ）、１．２１ （ｄ、Ｊ ＝ ６．８ Ｈｚ、３ Ｈ）、１．０５ （ｄ、Ｊ ＝ ６．８ Ｈｚ、３ Ｈ）。ｍ／ｚ （ＥＳＩ、＋ｖｅ）： ３９１．０ （Ｍ＋Ｈ）^＋。 Example 51
7- (2-fluorophenyl) -6-methyl-4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanil) phenyl)- 2 (1H) -Pteridinone

Step 1: 7- (2-Fluorophenyl) -1- (2-isopropylphenyl) -6-methylpteridine-2,4 (1H, 3H) -dione.
In a glass microwave reaction vessel, 6-chloro-7- (2-fluorophenyl) -1- (2-isopropylphenyl) pteridine-2,4 (1H, 3H) -dione (intermediate Y, 930 mg, 2. 27 mmol), [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) dichloromethane complex (166 mg, 0.28 mmol), trimethylboroxin (0.64 mL, 4.54 mmol, Sigma-Aldrich, St. Dichloromethane / aqueous solution (10: 1) (11 mL) of a mixture of Louis, MO, USA) and potassium carbonate (0.63 g, 4.54 mmol) was added. The reaction was degassed with nitrogen for 5 minutes and heated at 100 ° C. for 1.5 hours in an Emrys Optimizer microwave reactor (Biotage, Uppsala, Sweden). The reaction was cooled to room temperature and then partitioned between water (10 mL) and EtOAc (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-40% / heptane) and 7- (2-fluorophenyl) -1- (2-isopropylphenyl) -6-methylpteridine-2,4 (1H, 3H). ) -Obtained Zeon. ^{1 1} H NMR (400 MHz, chloroform-d) δ ppm 8.53 (br s, 1 H), 7.38-7.48 (m, 3 H), 7.30 (dt, J = 8.3, 4.2 Hz, 1 H), 7.08-7.20 (m, 4 H), 2.71 (quin, J = 6.8 Hz, 1 H), 2.61 (d, J = 2. 3 Hz, 3 H), 1.21 (d, J = 6.8 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H). m / z (ESI, + ve): 391.0 (M + H) ⁺ .

Step 2: 7- (2-fluorophenyl) -6-methyl-4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanil)) Phenyl) -2 (1H) -pteridinone.
7- (2-Fluorophenyl) -1- (2-isopropylphenyl) -6-methylpteridine-2,4 (1H, 3H) -dione (330 mg, 0.85 mmol) in acetonitrile solution (5 mL) with DIPEA ( After 0.252 mL, 1.44 mmol), phosphorus oxychloride (0.119 mL, 1.27 mmol) was added. The resulting solution was stirred at 60 ° C. for 1 hour and then concentrated. The residue was dissolved in DMF (5 mL), cooled to 0 ° C. and cannulated with DIPEA (0.51 mL, 2.88 mmol), followed by (S) -1- (3-methylpiperazin-1-yl) propa-2. -En-1-one 2,2,2-trifluoroacetate (544 mg, 0.93 mmol) was treated with a DMF solution (0.5 mL). The resulting mixture was stirred at 0 ° C. for 30 minutes and then gradually warmed to room temperature. The reaction was partitioned between EtOAc (10 mL) and water (10 mL, twice). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: MeOH 0-3% / DCM) and 7- (2-fluorophenyl) -6-methyl-4-((2S) -2-methyl-4- (2-propenoyl)). ) -1-Piperadinyl) -1- (2- (2-propanil) phenyl) -2 (1H) -pteridinone was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.48-7.57 (m, 1 H), 7.42 (dt, J = 7.7, 1.9 Hz, 1 H), 7 .32-7.37 (m, 2H), 7.20-7.31 (m, 3H), 7.10 (br dt, J = 7.1, 1.0 Hz, 1H), 6 .80-6.95 (m, 1H), 6.20 (br d, J = 16.6 Hz, 1 H), 5.75 (dd, J = 10.3, 2.0 Hz, 1 H) ), 4.66-5.57 (m, 1H), 4.13-4.46 (m, 3H), 3.44-3.73 (m, 3H), 2.56-2. 70 (m, 1H), 2.42 (s, 3H), 1.25 (br s, 3H), 1.09 (t, J = 6.1 Hz, 3H), 0.97 ( dd, J = 6.6, 1.7 Hz, 3H). m / z (ESI, + ve): 527.0 (M + H) ⁺ .

ステップ１：２，６−ジクロロ−５−メチルニコチン酸。
２，６−ジクロロ−５−メチルニコチン酸エチル（６．４９ｇ、２７．７ｍｍｏｌ、Ｐｈａｒｍａｂｌｏｃｋ Ｉｎｃ．、Ｓｕｎｎｙｖａｌｅ、ＣＡ、ＵＳＡ）のＴＦＡ溶液（３０ｍＬ）と５Ｎ ＨＣｌ（２４ｍＬ）の混合物を９０℃で１６時間加熱した。反応物を室温に冷却した後、部分的に濃縮した。水を加え、混合物をろ過した。ろ過後の固形物を回収し、真空下乾燥させ、２，６−ジクロロ−５−メチルニコチン酸を得た。ｍ／ｚ （ＥＳＩ、＋ｖｅ）： ２０５．９ （Ｍ＋Ｈ）^＋。 Example 52
7- (2-Fluoro-6-Hydroxyphenyl) -6-Methyl-4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2- (2-propanil) ) Phenyl) pyrido [2,3-d] pyrimidine-2 (1H) -on

Step 1: 2,6-dichloro-5-methylnicotinic acid.
A mixture of TFA solution (30 mL) and 5N HCl (24 mL) of ethyl 2,6-dichloro-5-methylnicotinate (6.49 g, 27.7 mmol, Pharmablock Inc., Sunnyvale, CA, USA) at 90 ° C. 16 Heated for hours. The reaction was cooled to room temperature and then partially concentrated. Water was added and the mixture was filtered. The solid matter after filtration was recovered and dried under vacuum to obtain 2,6-dichloro-5-methylnicotinic acid. m / z (ESI, + ve): 205.9 (M + H) ⁺ .

Step 2: 2,6-dichloro-5-methylnicotinamide.
Oxalyl chloride (2M DCM solution, 16.6 mL, 33.1 mmol) followed by DMF in an ice-cooled mixed DCM solution (30 mL) of 2,6-dichloro-5-methylnicotinic acid (4.55 g, 22.1 mmol). A few drops were added. The reaction mixture was gradually warmed to room temperature, stirred for 1 hour, and then concentrated. The residue was suspended in toluene (15 mL), cooled to 0 ° C. and treated with ammonium hydroxide (30%, 9.1 mL, 62 mmol). The reaction was stirred at room temperature for 30 minutes and then filtered. The filtered solid was washed with water and dried under vacuum to give 2,6-dichloro-5-methylnicotinamide. m / z (ESI, + ve): 204.9 (M + H) ⁺ .

Step 3: 2,6-dichloro-N-((2-isopropylphenyl) carbamoyl) -5-methylnicotinamide.
A mixed THF solution (10 mL) of 2,6-dichloro-5-methylnicotinamide (513 mg, 2.50 mmol) and oxalyl chloride (2 M DCM solution, 1.38 mL, 2.63 mmol) was heated at 65 ° C. for 1 hour. .. The reaction was cooled to room temperature and 2-isopropylaniline (0.36 mL, 2.63 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was partitioned between EtOAc (50 mL) and saturated aqueous sodium hydrogen carbonate solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in heptane / EtOAc (5: 1) and filtered. The solid matter after filtration was recovered to obtain 2,6-dichloro-N-((2-isopropylphenyl) carbamoyl) -5-methylnicotinamide. m / z (ESI, + ve): 365.8 (M + H) ⁺ .

Step 4: 7-Chloro-1- (2-isopropylphenyl) -6-methylpyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF solution, 4.54 mL, 4.54 mmol) was ice-cooled with 2,6-dichloro-N-((2-isopropylphenyl) carbamoyl) -5-methylnicotinamide (831 mg, 2.27 mmol). It was added to the mixed THF solution (10 mL) with a syringe. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was partitioned between EtOAc (20 mL) and saturated aqueous ammonium chloride solution (10 mL, twice). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in heptane / EtOAc (5: 1) and filtered. The solid matter after filtration was recovered to obtain 7-chloro-1- (2-isopropylphenyl) -6-methylpyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.36 (s, 1 H), 7.49 (dd, J = 8.5, 1.4 Hz, 1 H), 7.44 (td) , J = 6.8, 1.2 Hz, 1 H), 7.26-7.33 (m, 1 H), 7.23 (dd, J = 7.9, 1.7 Hz, 1 H) , 2.68 (quin, J = 6.8 Hz, 1H), 2.34 (s, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.02 (d) , J = 6.6 Hz, 3 H). m / z (ESI, + ve): 329.9 (M + H) ⁺ .

Step 5: (S) -4- (7-chloro-1- (2-isopropylphenyl) -6-methyl-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl)- 3-Methylpiperazine-1-carboxylate tert-butyl.
In an acetonitrile solution (5 mL) of 7-chloro-1- (2-isopropylphenyl) -6-methylpyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (444 mg, 1.35 mmol). DIPEA (0.70 mL, 4.04 mmol) was followed by phosphorus oxychloride (0.125 mL, 1.35 mmol). The resulting solution was stirred at 80 ° C. for 2 hours and then concentrated. The residue was dissolved in acetonitrile (5 mL) and cooled to 0 ° C., DIPEA (0.70 mL, 4.04 mmol) followed by (S) -4-N-Boc-2-methylpiperazine (297 mg, 1.48 mmol, Combi). -Blocks, Inc., San Diego, CA, USA). The resulting mixture was stirred at 0 ° C. for 30 minutes and then gradually warmed to room temperature. The reaction was partitioned between EtOAc (10 mL) and water (10 mL, twice). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-30% / heptane) and (S) -4- (7-chloro-1- (2-isopropylphenyl) -6-. Methyl-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylate tert-butyl was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.16 (d, J = 16.2 Hz, 1 H), 7.47 (dd, J = 6.8, 1.2 Hz, 1 H) ), 7.41 (br t, J = 7.3 Hz, 1 H), 7.28 (dt, J = 7.7, 1.2 Hz, 1 H), 7.09 (dt, J = 7) 8.8, 1.6 Hz, 1H) 4.70-4.90 (m, 1H) 3.89-4.20 (m, 2H) 3.97-4.09 (m, 2H) 3.76-3.88 (m, 1H), 3.53-3.72 (m, 1H), 2.44 (td, J = 6.8, 4.9 Hz, 1 H) 2.35 (d, J = 0.8 Hz, 3H), 1.45 (s, 9H), 1.25 (br s, 3H), 1.06 (d, J = 6) .8, 3 H), 1.02 (dd, J = 6.8, 1.7 Hz, 3 H). m / z (ESI, + ve): 511.9 (M + H) ⁺ .

Step 6: (3S) -4- (7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropylphenyl) -6-methyl-2-oxo-1,2-dihydropyrido [2,3-] d] Pyrimidine-4-yl) -3-methylpiperazine-1-carboxylate tert-butyl.
(S) -4- (7-Chloro-1- (2-isopropylphenyl) -6-methyl-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methyl Tert-Butyl piperazin-1-carboxylic acid (458 mg, 0.89 mmol), potassium acetate (439 mg, 4.47 mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (418 mg, 2.68 mmol, Combi-Blocks, San Diego, CA, USA), and a 1,4-dioxane solution in which a mixture of [1,1'-bis (diphenylphosphino) ferrocene] -dichloropalladium (II) dichloromethane complex (65 mg, 0.09 mmol) was dissolved. A mixture of (7 mL) and water (0.05) was heated at 90 ° C. for 2 hours. The reaction was cooled to room temperature and then partitioned between saturated aqueous sodium hydrogen carbonate solution (15 mL) and EtOAc (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-30% / heptane) and (3S) -4- (7- (2-fluoro-6-hydroxyphenyl) -1-. (2-Isopropylphenyl) -6-methyl-2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylate tert-butyl was obtained. m / z (ESI, + ve): 587.9 (M + H) ⁺ .

Step 7: 7- (2-Fluoro-6-hydroxyphenyl) -6-methyl-4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) -1- (2-( 2-Propanil) Phenyl) Pyrid [2,3-d] Pyrimidine-2 (1H) -one.
Trifluoroacetic acid (1.7 mL, 14.7 mmol) with (3S) -4- (7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropylphenyl) -6-methyl-2-oxo -1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylate tert-butyl (288 mg, 0.49 mmol) was added to a DCM solution (5 mL). The resulting mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in DCM (3 mL), cooled to 0 ° C. and treated with DIPEA (0.34 mL, 1.96 mmol) followed by acryloyl chloride (0.042 mL, 0.51 mmol) in DCM solution (0.5 mL). .. The reaction mixture was warmed to room temperature and stirred for 30 minutes, then the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptane) and 7- (2-fluoro-6-hydroxyphenyl) -6-methyl-1- (2-). Methyl-6- (2-propanyl) phenyl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H)- Got on. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.94 (s, 1H), 8.10-8.19 (m, 1H), 7.38 (dd, J = 7.5, 1) .0 Hz, 1 H), 7.31 (td, J = 7.1, 0.8 Hz, 1 H), 7.16-7.24 (m, 2 H), 7.06 (br dt, J = 7.9, 1.9 Hz, 1H), 6.75-6.97 (m, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.64 ( t, J = 8.8 Hz, 1 H), 6.21 (br dd, J = 16.9, 5.7 Hz, 1 H), 5.76 (dd, J = 10.2, 2.5) Hz, 1H), 4.76-4.98 (m, 1H), 4.10-4.51 (m, 2H), 3.24-3.81 (m, 4H), 2. 43-2.49 (m, 1H), 2.12 (d, J = 2.9 Hz, 3H), 1.22-1.33 (m, 3H), 1.05 (d, J) = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H). m / z (ESI, + ve): 541.8 (M + H) ⁺ .

ステップ１：２，５，６−トリクロロ−Ｎ−（（１−イソプロピル−４−メチル−１Ｈ−ピラゾール−５−イル）カルバモイル）ニコチンアミド。
２，５，６−トリクロロニコチンアミド（中間体Ｐ、２．４３ｇ、１０．８ｍｍｏｌ）の混合ＴＨＦ溶液（２１．５ｍＬ）に室温で塩化オキサリル溶液（２Ｍ ＤＣＭ溶液、５．７０ｍＬ、１１．４ｍｍｏｌ）を加えた。得られた混合物を６５℃で３時間加熱し、その後、加熱を中止して反応物を０℃に冷却した。１−イソプロピル−４−メチル−１Ｈ−ピラゾール−５−アミン（１．５０ｇ、１０．８ｍｍｏｌ、ＣｈｅｍＢｒｉｄｇｅ、Ｓａｎ Ｄｉｅｇｏ、ＣＡ、ＵＳＡ）のＴＨＦ溶液（１５ｍＬ）をカニューレで加えた。得られた混合物を０℃で３０分間撹拌し、その後、室温に昇温させ、さらに１６時間撹拌した。反応混合物をろ過し、ろ過後の固形物を回収してアセトニトリル（２０ｍＬ）で洗浄し、２，５，６−トリクロロ−Ｎ−（（１−イソプロピル−４−メチル−１Ｈ−ピラゾール−５−イル）カルバモイル）ニコチンアミドを得た。^１Ｈ ＮＭＲ （４００ ＭＨｚ、ＤＭＳＯ−ｄ_６） δ ｐｐｍ １１．３９ （ｂｒ ｓ、１ Ｈ）、９．５１ （ｂｒ ｓ、１ Ｈ）、８．６２ （ｓ、１ Ｈ）、７．２９ （ｓ、１ Ｈ）、４．３３−４．４４ （ｍ、１ Ｈ）、１．８７ （ｓ、３ Ｈ）、１．３３ （ｄ、Ｊ ＝ ６．６ Ｈｚ、６ Ｈ）。 ｍ／ｚ （ＥＳＩ、＋ｖｅ イオン）： ３８９．９ （Ｍ＋Ｈ）^＋。 Example 53
6-Chloro-7- (2-fluorophenyl) -1- (4-methyl-1- (2-propanil) -1H-pyrazole-5-yl) -4-((2S) -2-methyl-4- (2-Propenoyl) -1-piperazinyl) Pyrazole [2,3-d] Pyrimidine-2 (1H) -on

Step 1: 2,5,6-trichloro-N-((1-isopropyl-4-methyl-1H-pyrazole-5-yl) carbamoyl) nicotinamide.
Oxalyl chloride solution (2M DCM solution, 5.70 mL, 11.4 mmol) in a mixed THF solution (21.5 mL) of 2,5,6-trichloronicotinamide (intermediate P, 2.43 g, 10.8 mmol) at room temperature. Was added. The resulting mixture was heated at 65 ° C. for 3 hours, after which the heating was stopped and the reaction was cooled to 0 ° C. A solution of 1-isopropyl-4-methyl-1H-pyrazole-5-amine (1.50 g, 10.8 mmol, ChemBridge, San Diego, CA, USA) in THF (15 mL) was added by cannula. The resulting mixture was stirred at 0 ° C. for 30 minutes, then warmed to room temperature and further stirred for 16 hours. The reaction mixture is filtered, the filtered solid is collected and washed with acetonitrile (20 mL) and 2,5,6-trichloro-N-((1-isopropyl-4-methyl-1H-pyrazole-5-yl)). ) Carbamoyl) Nicotinamide was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.39 (br s, 1 H), 9.51 (br s, 1 H), 8.62 (s, 1 H), 7.29 ( s, 1H), 4.33-4.44 (m, 1H), 1.87 (s, 3H), 1.33 (d, J = 6.6 Hz, 6H). m / z (ESI, + ve ion): 389.9 (M + H) ⁺ .

Step 2: 6,7-Dichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione.
KHMDS (1M THF solution, 18.0 mL, 18.0 mmol) with 2,5,6-trichloro-N-((1-isopropyl-4-methyl-1H-pyrazol-5-yl) carbamoyl) nicotinamide (3) It was slowly added to an ice-cooled mixed THF solution (30 mL) of .52 g, 9.0 mmol) with a syringe. After 10 minutes, the resulting mixture was warmed to room temperature and stirred for 18 hours. The reaction of the resulting slurry was stopped with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL), followed by extraction with EtOAc (50 mL, twice). The combined organic layers were washed with saline (50 mL), dried over anhydrous sodium sulfate and concentrated, and 6,7-dichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) pyridod. [2,3-d] Pyrimidine-2,4 (1H, 3H) -dione was obtained. This material was used in subsequent steps without further purification. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.22 (br s, 1 H), 8.55 (s, 1 H), 7.45 (s, 1 H), 4.22-4 .34 (m, 1 H), 1.78 (s, 3 H), 1.25 (t, J = 6.6 Hz, 6 H). m / z (ESI, + ve ion): 353.9 (M + H) ⁺ .

Step 3: 4,6,7-Trichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one.
6,7-Dichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) pyrido [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (3.19 g, Phosphorus oxychloride (1.68 mL, 18.0 mmol) was added to an acetonitrile solution (60 mL) of 9.0 mmol) and DIPEA (4.71 mL, 27.0 mmol). The resulting mixture was heated at 80 ° C. for 30 minutes, then cooled to room temperature and concentrated to concentrate 4,6,7-trichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl). Pyrazole [2,3-d] pyrimidin-2 (1H) -on was obtained. This material was used in subsequent steps without further purification.

Step 4: 4- (6,7-dichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin- 4-Il) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl.
4,6,7-Trichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) pyrido [2,3-d] pyrimidine-2 (1H) -one (3.36 g, 9. DIPEA (4.71 mL, 27.1 mmol) in THF solution (45 mL) (0 mmol), followed by (S) -4-N-Boc-2-methylpiperazine (2.71 g, 13.6 mmol, Combi-Blocks, Inc. ., San Diego, CA, USA) was added. The resulting mixture was stirred at room temperature for 1 hour, then the reaction was stopped with ice-cold saturated aqueous sodium hydrogen carbonate solution (100 mL) and extracted with EtOAc (100 mL, then 50 mL twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc-EtOH (3: 1) 0-50% / heptane) and 4- (6,7-dichloro-1- (1-isopropyl-4-methyl-1H-). Pyrazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid (S) -tert-butyl was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.43 (d, J = 19.1 Hz, 1 H), 7.42 (s, 1 H), 4.77-4.98 (m) , 1H), 4.15 (br dd, J = 26.7, 13.5 Hz, 1H), 3.61-4.07 (m, 4H), 2.94-3.28 (m) , 2 H), 1.72 (d, J = 5.2 Hz, 3 H), 1.44 (s, 9 H), 1.32 (br dd, J = 13.0, 6.7 Hz, 3 H), 1.21-1.28 (m, 6 H). m / z (ESI, + ve ion): 536.0 (M + H) ⁺ .

Step 5: (S) -4- (6-chloro-7- (2-fluorophenyl) -1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) -2-oxo-1,2 -Dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate tert-butyl.
(S) -4- (6,7-dichloro-1- (1-isopropyl-4-methyl-1H-pyrazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidine -4-yl) -3-methylpiperazin-1-carboxylate tert-butyl (703 mg, 1.31 mmol), (2-fluorophenyl) boronic acid (330 mg, 2.36 mmol, Combi-Blocks, San Diego, CA, With a 1,4-dioxane solution (3.5 mL) in which a mixture of USA), anhydrous sodium carbonate (416 mg, 3.93 mmol), and tetrakis (triphenylphosphine) palladium (0) (151 mg, 0.13 mmol) was dissolved. The mixture with water (0.87 mL) was heated at 80 ° C. for 2 hours. The reaction was concentrated and the residue was purified by silica gel chromatography (eluent: EtOAc 0-100% / heptane) and (S) -4- (6-chloro-7- (2-fluorophenyl) -1- (1). −Isopropyl-4-methyl-1H-pyrazole-5-yl) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) -3-methylpiperazin-1-carboxylic acid tert- Obtained butyl. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.41 (d, J = 8.9 Hz, 1 H), 7.50-7.66 (m, 1 H), 7.24-7 .37 (m, 4H), 4.92 (br s, 1H), 4.24 (brt, J = 12.4 Hz, 1H), 3.95-4.12 (m, 2H) ), 3.67-3.89 (m, 2H), 3.00-3.29 (m, 2H), 1.70 (s, 3H), 1.45 (s, 9H), 1.36 (t, J = 6.6 Hz, 3 H), 1.14-1.28 (m, 6 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -113.95 (d, J = 6.9 Hz, 1 F). m / z (ESI, + ve ion): 596.0 (M + H) ⁺ .

Step 6: 6-Chloro-7- (2-fluorophenyl) -1- (4-methyl-1- (2-propanil) -1H-pyrazole-5-yl) -4-((2S) -2-methyl -4- (2-propenoyl) -1-piperazinyl) pyrido [2,3-d] pyrimidin-2 (1H) -on.
Trifluoroacetic acid (7.4 mL, 63.6 mmol), (S) -4- (6-chloro-7- (2-fluorophenyl) -1- (1-isopropyl-4-methyl-1H-pyrazole-5) -Il) -2-oxo-1,2-dihydropyrido [2,3-d] pyrimidin-4-yl) tert-butyl-3-methylpiperazin-1-carboxylate (532 mg, 0.74 mmol) in DCM solution ( 7.4 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCM (7.4 mL), cooled to 0 ° C. and treated with DIPEA (1.28 mL, 7.35 mmol) followed by acryloyl chloride (0.2 M DCM solution, 3.67 mL, 0.74 mmol). .. The resulting mixture was stirred at 0 ° C. for 20 minutes, then the reaction was stopped with saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted with DCM (50 mL, twice). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc 0-50% / heptane, then DCM-MeOH (4: 1) 0-50% / DCM) and 6-chloro-7- (2-fluorophenyl)-. 1- (4-Methyl-1- (2-propanyl) -1H-pyrazole-5-yl) -4-((2S) -2-methyl-4- (2-propenoyl) -1-piperazinyl) pyrido [2 , 3-d] Pyrimidin-2 (1H) -on was obtained. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.44 (br d, J = 7.5 Hz, 1 H), 7.50-7.59 (m, 1 H), 7.23- 7.41 (m, 4H), 6.77-6.93 (m, 1H), 6.21 (br d, J = 16.4 Hz, 1H), 5.71-5.81 ( m, 1H), 4.96 (br s, 1H), 4.22-4.46 (m, 2H), 3.96-4.21 (m, 2H), 3.37-3 .89 (m, 2H), 3.00-3.28 (m, 1H), 1.71 (d, J = 2.5 Hz, 3H), 1.34 (t, J = 6. 8 Hz, 3 H), 1.12-1.29 (m, 6 H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ ppm -113.96 (d, J = 9.5 Hz, 1 F). m / z (ESI, + ve ion): 550.2 (M + H) ⁺ .

Bioassay Data For the compounds in Table 15, the following assay conditions were used.

Conjugated nucleotide exchange assay: Purified GDP-conjugated KRAS protein (amino acids 1-169) containing both G12C and C118A amino acid substitutions and N-terminal His tags in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl ₂ , and Pre-incubated in 0.01% Triton X-100) for 2 hours using compound dose reaction titration. After preincubation with the compound, purified SOS protein (amino acids 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional hour. Purified GST-tagged cRAF (amino acids 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were placed in assay wells to determine the degree of SOS-mediated nucleotide exchange inhibition. In addition, it was incubated for 10 minutes. Thereafter, the assay plates read at PerkinElmer EnVision Multilabel Reader using AlphaScreen (TM) method, using a 4 parameter logistic model to analyze the data and _{IC 50} values were calculated.

Phospho-ERK1 / 2 MSD assay: MIA PaCa-2 (ATCC® CRL-1420 ™) cells and A549 (ATCC® CCL-185 ™) cells in 10% fetal bovine serum ( The cells were cultured in RPMI1640 medium (ThermoFisher Scientific 11875093) containing ThermoFisher Scientific 16000044) and 1 × penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). 16 hours prior to compound treatment, MIA PaCa-2 or A549 cells were seeded on 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37 ° C. and 5% CO ₂ . Compound dose-response titrations were diluted in growth medium, added to the appropriate wells of cell culture plates, and then incubated at 37 ° C. for 4 hours at 5% CO ₂ . After compound treatment, cells were stimulated with 10 ng / mL EGF (Roche 11376454001) for 10 minutes, washed with Ca ²⁺ , Mg 2 ⁺ -free ice-cold dalbecolinic acid buffered saline (ThermoFisher Scientific 14190144) and then washed. , RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0) containing a protease inhibitor (Roche 4693132001) and a phosphatase inhibitor (Roche 4906837001). It was dissolved in 5.5% sodium dodecyl sulfate). Cell lysates were cryopreserved overnight at −80 ° C. The Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) was used according to the manufacturer's protocol to evaluate ERK1 / 2 phosphorylation of the compound-treated lysates. Read the assay plates Meso Scale Discovery Sector Imager 6000, 4- parameters using logistic model to analyze the data and _{IC 50} values were calculated.

For the compounds in Table 16, the following assay conditions were used.

Conjugated nucleotide exchange assay: Purified GDP-conjugated KRAS protein (amino acids 1-169) containing both G12C and C118A amino acid substitutions and N-terminal His tags in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl ₂ , and Pre-incubated for 5 minutes using compound dose reaction titration in 0.01% Triton X-100). After preincubation with the compound, purified SOS protein (amino acids 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 minutes. Purified GST-tagged cRAF (amino acids 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were placed in assay wells to determine the degree of SOS-mediated nucleotide exchange inhibition. In addition, it was incubated for 5 minutes. Thereafter, the assay plates read at PerkinElmer EnVision Multilabel Reader using AlphaScreen (TM) method, using a 4 parameter logistic model to analyze the data and _{IC 50} values were calculated.

Phospho-ERK1 / 2 MSD assay: MIA PaCa-2 (ATCC® CRL-1420 ™) cells and A549 (ATCC® CCL-185 ™) cells in 10% fetal bovine serum ( The cells were cultured in RPMI1640 medium (ThermoFisher Scientific 11875093) containing ThermoFisher Scientific 16000044) and 1 × penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). 16 hours prior to compound treatment, MIA PaCa-2 or A549 cells were seeded on 96-well cell culture plates at a density of 25,000 cells / well and incubated at 37 ° C. and 5% CO ₂ . Compound dose-response titrations were diluted in growth medium, added to the appropriate wells of cell culture plates, and then incubated at 37 ° C. for 2 hours at 5% CO ₂ . After compound treatment, cells were stimulated with 10 ng / mL EGF (Roche 11376454001) for 10 minutes, washed with Ca ²⁺ , Mg 2 ⁺ -free ice-cold dalbecolinic acid buffered saline (ThermoFisher Scientific 14190144) and then washed. , RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0) containing a protease inhibitor (Roche 4693132001) and a phosphatase inhibitor (Roche 4906837001). It was dissolved in 5.5% sodium dodecyl sulfate). The Phospho-ERK1 / 2 Whole Cell Lysate kit (Meso Scale Discovery K151DWD) was used according to the manufacturer's protocol to evaluate ERK1 / 2 phosphorylation of the compound-treated lysates. Read the assay plates Meso Scale Discovery Sector Imager 6000, 4- parameters using logistic model to analyze the data and _{IC 50} values were calculated.

The present invention has been described in the context of preferred embodiments. However, it should be understood that the present invention is not limited to the disclosed embodiments. Although embodiments of the present invention are described herein, it will be appreciated that various modifications can be made by those skilled in the art. Such changes are embraced by the following claims.

Claims (32)

Compounds with structures selected from,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. Construction

Compounds,
Or its stereoisomer, its atropisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its atropisomer. The compound according to any one of claims 1 to 16, which is in a pharmaceutically acceptable salt form. A pharmaceutical preparation comprising any one or more of the compounds according to claims 1 to 17 and a pharmaceutically acceptable excipient. A method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound according to any one of claims 1-17 or the composition according to claim 18. A method for treating cancer in a subject, wherein the compound according to any one of claims 1 to 17 in a therapeutically effective amount or the composition according to claim 18 in a therapeutically effective amount with respect to the subject. Said method comprising administering. The method of claim 20, wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer. The method of claim 20, wherein the cancer is lung cancer. The method of claim 20, wherein the cancer is pancreatic cancer. The method of claim 20, wherein the cancer is colorectal cancer. 20. The method of claim 20, further comprising administering to the patient in need of a therapeutically effective amount of a further pharmaceutically active compound. 25. The method of claim 25, wherein the further pharmaceutically active compound is carfilzomib. 25. The method of claim 25, wherein the further pharmaceutically active compound is cytarabine. Use of the compound according to any one of claims 1-18 for treating cancer in a subject. The compound according to any one of claims 1 to 16 in the preparation of a drug for treating cancer. The compound according to claim 29, wherein the cancer is a hematological malignancy. The compound according to any one of claims 1 to 16, for treating cancer. The compound according to claim 31, wherein the cancer is a malignant disease of the blood system.